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AU2005202144B2 - Quinuclidine derivatives and their use as muscarinic M3 receptor ligands - Google Patents

Quinuclidine derivatives and their use as muscarinic M3 receptor ligands Download PDF

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AU2005202144B2
AU2005202144B2 AU2005202144A AU2005202144A AU2005202144B2 AU 2005202144 B2 AU2005202144 B2 AU 2005202144B2 AU 2005202144 A AU2005202144 A AU 2005202144A AU 2005202144 A AU2005202144 A AU 2005202144A AU 2005202144 B2 AU2005202144 B2 AU 2005202144B2
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octane
hydroxy
nmr
yield
title compound
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Maria Antonia Buil Albero
Dolors Fernandez Forner
Maria Prat Quinones
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Almirall SA
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Priority claimed from AU64330/00A external-priority patent/AU779881C/en
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    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

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Description

AUSTRALIA
00 PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: Almirall Prodesfarma AG ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Nicholson Street Melbourne VIC 3000 INVENTION TITLE: "Quinuclidine derivatives and their use as muscarinic M 3 receptor ligands" The following statement is a full description of this invention, including the best method of performing it known to us: 1 NOVEL QUINUCLIDINE DERIVATIVES AND MEDICINAL COMPOSITIONS CONTAINING THE SAME 0 0 This is a divisional of Australian Patent Application No.
779,881 (64330/00), the entire contents of which are incorporated herein by reference.
This invention relates to new therapeutically useful quinuclidine Sderivatives, to some processes for their preparation and to O pharmaceutical compositions containing them.
The novel structures according to the invention are antimuscarinic agents with a potent and long lasting effect. In particular, these compounds show high affinity for muscarinic M 3 receptors(Hm3).
In accordance with their nature as M 3 antagonists, the new compounds are suitable for treating the following diseases: respiratory disorders such as chronic obstructive pulmonary disease(COPD), chronic bronchitis, bronchial hyperreactivity, asthma and rhinitis; urological disorders such as urinary incontinence, pollakinuria in neuripenia pollakinuria, neurogenic or unstable bladder, cystospasm and chronic cystitis; and gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration.
The compounds claimed are also useful for the treatment of the respiratory diseases detailed above in association with P agonists, steroids, antiallergic drugs or phosphodiesterase IV inhibitors.
Compounds of the present invention may also be expected to have anti-tussive properties.
Depending on their nature the new compounds may be suitable for treating vagally induced sinus bradycardia.
Compounds with related structures have been described as antispasmodics and anti-cholinergic agents in several patents.
-IA-
For examol e, in patent FR 201296.4 are described quinuclidinol 00 derivatives of the formula
R
Ri Cl R2 CI 0
N
00 in which R is H, OH or an alkyl group having 1 to 4 carbon atoms; R 1 is a phenyl or thienyl group; and R, is a cyclohexyl, cyclopentyl or thienyl group, or, when R is H, R, and R 2 together with the carbon atom to which they are attached, form a tricyclic group of the formula: in which X is or or an acid addition or quaternary ammonium salt thereof.
EP- 418716 describes thienyl carboxylate esters of formula wherein A is a group
(CH
2 Q' Q
(CH
2 m and n 1 or 2 0 Q is a -CH 2
-CH
2 -CHI-CH,-CH-, -CH=CH-, group Q'is a =NR or NRR' group; R, is a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl group, optionally substituted; R, is H, OH, CI-C, alkoxy or C 1 alkyl and Ra is H, F, Cl, CH 3 or -NR.
US 5,654,314 describes compounds of formula: 3 00 R1 Ph tO N R' S wherein R is an optionally halo- or hydroxy-substituted C1.. alkyl C group; R is a C1- 4 alkyl group; or R and R' together form a C4_6 alkylene group; X- is an anion; and R, is H, OH, -CH 2 OH, C1-, alkyl or CI4 alkoxy.
The present invention provides new quinuclidine derivatives with potent antagonist activity at muscarinic M 3 receptors which have the chemical structure described in formula R1 0 B C (CH 2 N(CH
O
R2 22T O R3
X
(I)
wherein: Sis a phenyl ring, a C, to C 9 heteroaromatic group containing one or more heteroatoms (preferably selected from nitrogen, oxygen and sulphur atoms), or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group;
R
2 and R' each independently represent a hydrogen or halogen atom, or a hydroxy group, or a phenyl, -NR'R
S
-NHCOR', -CONR'R 5 -CN, -NO 2 -COOR' or -CF3 group,or a straight or branched lower alkyl group which may optionally be substituted, for example, with a hydroxy or alkoxy group, wherein R and R 5 each independently represent a hydrogen atom, straight or branched lower alkyl group, or together form an alicyclic ring; or R' and R 2 together form an aromatic, alicyclic or heterocyclic ring; n is an integer from 0 to 4; I 4 A represents a -CH -CH=CR 6 -CR6=CH-, -CR 6
R
7
SO
2 or -NR6- group, wherein R 6 and R 7 each independently represent a hydrogen atom, straight or branched lower alkyl group, or 00
R
6 and R' together form an alicyclic ring.; m is an integer from 0 to 8; provided that when m 0, A is not p is an integer from 1 to 2 and the substitution in the azoniabicyclic ring may be in the 2, 3 or 4 position including all possible configurations of the asymmetric carbons; SB represents a group of formula i) or ii): i) ii) SR8 R8 R9y I R 10
Q
wherein R' 0 represents a hydrogen atom, a hydroxy or methyl group; and
R
8 and R 9 each independently represents R11 R11 R11 R11 SR1O wherein R 1 represents a hydrogen or halogen atom, or a straight or branched lower alkyl group and Q represents a single bond, -CH 2
-CH
2
CH
2 -0-CH 2
-S-CH
2 or -CH=CH-, and when i) or ii) contain a chiral centre they may represent either configuration; X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
In the quaternary ammonium compounds of the present invention represented by formula an equivalent of an anion (X-)is associated with the positive charge of the N atom. X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, and organic acids such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, Cl mandelate, methanesulfonate and p-toluenesulfonate. X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, S acetate, maleate, oxalate or succinate. More preferably X- is chloride, bromide or trifluoroacetate.
The compounds of the present invention represented by the formula described above, which may have one or more assymetric carbons, ,q include all the possible stereoisomers. The single isomers and mixtures of the isomers fall within the scope of the present invention.
l n If any of R 1 to R 7 or R n represents an alkyl group, it is O preferred that said alkyl group contains 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms. In particular it is preferred that any alkyl group is represented by a methyl, ethyl, propyl, including i-propyl, butyl including a n-butyl, sec-butyl and tertbutyl.
The alicyclic and heterocyclic rings mentioned in relation to formula preferably comprise from 3 to 10, preferably from 5 to 7 members. The aromatic rings mentioned in relation to formula above preferably contain from 6 to 14, preferably 6 or 10 members.
Preferred compounds of formula are those wherein represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5, 6, 7, 8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl or benzothiazolyl group, in particular a phenyl, pyrrolyl, or thienyl group; R 1
R
2 and R 3 each independently represent a hydrogen or halogen atom, or a hydroxyl, methyl, tert-butyl, -CH20H, 3-hydroxypropyl, -OMe, -NMe 2 -NHCOMe, -CONH2, -CN, -NO 2 -COOMe or -CF3 group, in particular a hydrogen atom, a hydroxy group or a halogen atom, wherein the halogen atom is preferably fluorine; n 0 or 1; m is an integer from 1 to 6, particularly 1, 2 or 3; A represents a -CH 2 -CH=CH-, -NH-, -NMe-, or group, in particular a -CH 2 -CH=CH- or group.
It is also preferred that p 2 and the substituent group -OC(O)B attached to the azoniabicyclo[2.2.2]octane is at the 3 position, preferably having the configuration.
Further preferred compounds of formula I are those wherein B is a group of formula i) or ii) as defined above wherein, if B is a group of formula R 8 and R 9 each independently represent a phenyl, 2thienyl, 3-thienyl, 2-fury! or 3-furyl group, wherein is hydrogen Satom; and, If B is a group of formula (ii) ,Q represents a single bond, 00 -CH 2
-CH
2 or group, in particular a single bond, -CH 2
-CH
2 or group, most preferably a single bond or group and in any case R" 0 is a hydrogen atom or a hydroxy or methyl group; __and when i) or ii) contain a chiral centre they may represent either the or the configuration.
Most preferably the -00(0)B group in formula i s di-phenylacetoxy, 2-hydroxy-2 ,2-diphenyl-acetoxy, 2-diphenylpropionyloxy, 2-hydroxy- 2-phenyl-2-thien-2-yl-acetoxy, 2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2, 2-dithien-2-ylacetoxy, 2-hydroxy-2, 2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy, 9 -h y d r o x y 9 H] fl1u o re n e -9 -c ar b on y l ox y 9-methyl-9[H]-fluorene-9-carbonyloxy, 9(H]-xanthene-9-carbonyloxy, 9hy d r ox y-9 xa nt h ene-9-c ar b onylo x y 9 m et hyl1-9 H] -xant he ne-9-c ar b onylo x y 2 2 2-b i s 4-fl1u o r o p h en y I 2 -h y d r o x y a ce t o xy 2-hydroxy-2,2-di-p-tolylacetoxy, 2,2-difuran-2-yl-2-hydroxy acetoxy, 2,2-dithien-2-ylpropionyloxy, lO-dihydroanthracene-9-carbonyloxy, 9 H] th io x an th en e- 9 -c ar b onyl1o x y, o r Especially preferred compounds are those wherein the -0C(0)B group in formula is diphenylacetoxy, 2-hydroxy-2 ,2-diphenyl-acetoxy, 2, 2-diphenylpropiJonyloxy, 2-hydroxy-2--phenyl-2-thien-2-yl-acetoxy,.
2-furan-2)-yl-2 hydroxy-2-phenylacetoxy, 2, 2-dithien-2-ylacetoxy, 2 -hydroxy-2, 2--di -thien- 2--yl ace toxy, 2,-hydroxy-2,2 -di-thien-3-ylacetoxy, 9 -h y dr ox y-9 H] flIuo re ne- 9 -c ar b on ylo x y 9-methyl-9 -fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy, 9 -h yd r ox y-9 [H]3 xan t hen e-9 ca r b on y1o xy o r 9-methyl-9 (H]-xanthene-9-carbonyloxy.
The most preferred compounds of formula are those wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl, 3-[2-hydroxyphenoxylpropyl, 3-[4-fluorophenoxylpropyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl, 3-thien-2ylpropyl, 3-phenylaminopropyl, 3- (methylphenylamino)propyl, 3-p h e nyl1s ulf an yIp rop yl1 3 -o -t olylo x ypr o p y1 00 3- (2 6 -t r irme t hylp h enlo'xy pr op y1 3-(2--tert-butyl-6-methyJlphefloxy)propyl, 3- (biphenyl-4-yloxy)propyl, 3- 6, 7, 8-tetrahydronaphthalen-2-yloxY) -propyl, 3- (naphthalen-2-yloxy) propyl, 3-(naphthalen-l-yloxy)propyl, 3- (2-chlorophenoxy)propyl, 3-(2,4-difluorophenoxy)propyl, 3-(3-trifluoromethyl phenoxy)propyl, 3-(3-cyanophenoxy)propyl, 3-(4-cyaflophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(4-rnethoxyphefloxy)propyl, C1 3-(benzo[l,3]dioxol-5-yloxy)propyl, 3-(2-carbamoylphenoxy)propyl, 3-(3-dimethylaminophenoxy)propyl, 3-(4-nitrophenoxy)propy-, 3- (3-nitropherioxy)propyl, 3- (4-acetylaminophefloxy)propyl, 3-(3-methoxycarbonylphenoxy)propyJ., 3-14-(3-hydroxypropyl) phenoxylpropyl, 3- (2-hydroxymethylp hefloxy)propyl, 3-(3-hydroxymethylphenoxy) propyl, 3- (4-hydroxyrnethylphenoxy)propyl, 3-(2-hydroxyphenoxy)propyl, 3-(4-hydroxyphenoxy)propy., 3-(3-hydroxyphenoxy)propyl, 4-oxo-4-thien-2- ylbutyl, 3-(l-methyl-[lH]imidazol-2-ylsulfanyl)propyl, 3-(benzothiazol-2-yloxy)propyl, 3-benzyloxypropyl, 6-(4-phenylbutoxy)hexyl, 4-phenoxybutyl, or 2-benzyloxyethyl group. Especially preferred compounds are those wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4phenylbutyl, 3-phenyipropyl, 3-[2-hydroxyphenoxylpropyl, 3-[4fluorophenoxyjpropyl, 2-benzyloxyethyl, 3-pyrrol-l-ylpropyl, 2-thien-2ylethyl or 3-thien-2-ylpropyl group.
The following compounds are intended to illustrate but not to limit the scope of the present invention.
3(R) -Diphenylacetoxy-l- (3-phenoxy-propyl) -1-azoni-abicyclo[2 octane; bromide 3(R)-(-yrx -ih n l ae y)l (-hnxp oy )la o ib cyclo [2 .2 .2]octane; bromide 3C(R) 2-Diphenylpropionyloxy) (3-phenoxypropyl) -1-azoniabicyclo [2.
2.2]octane; bromide 3 (2 -Hydroxy- 2-phenyl -2 -thien-2 -yl -ace toxY) (3-phenoxypropyl) -1azonia-bicyclo[2.2.2]octane; bromide 8 S3(R)-(2-Fcuran-2-yi-92-hydroxy-2-phenyiacetoxy)-1-.(3-phenyialiyl)-l-azo S niabicyclo[2.2.2]octane; bromide 00 3 (R)-(2-Furan-2-yl-2'-hydroxy-21-phenylacetoxy)-l-(2-pheloxyethyl)-1-azo niabicycio[2.2.2]octane; bromide 3 (R)-(2-Furan-2-yl--2-hvdroxy-2-phenylacetoxy)-l-(3-pheloxypropyl)-l-azo niabicyclo octane; bromide 3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropy-) -1-azoniabicyclo C1 2.2.2]octane; bromide 3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-l-phelethyl-l-azoniabicy ri clo[2.2.2]octane; bromide 3CR)- (2-H-ydroxy-2, 2-di-thien-2-ylacetoxy) -1-(4-phenylbutyl) -1-azonia bicyclot2.2.2]octane; bromide 3 (2-Hydroxy-2, 2-dithien-2-ylacetoxy) (3-phen'oxypropyl) -1-azoniabicyclo[2.2.2]octane; bromide 1-(3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylaceto xy)-l-azoniabicyclo[2.2.2]octane; chloride 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-l-[3-C2-hydroxyphenoxy)pro pyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate 3 (2-Hydroxy-2, 2-dithien-2--yiacetoxy) (3-pyrrol-1-ylpropyl) -1-a z.onia-bicyclo[2.2.2oct.ane; trifluoroacetate 3 (2-Hydroxy-2, 2-dithien-2--yiacetoxy) (2 -thien- 2-yl ethyl) -1-azo niabicycio[2.2.2]octane; bromide 3(R) -(2-Hydroxy-2, 2-dithien-2-ylacetoxy) -1-(3-thien-2-ylpropyl) -1-a zoniabicyclo[2.2.2]octane; bromide 1- (2-Benzyloxyethyl) -3 -(2-hydroxy-2, 2-dithien-2-ylacetoxy) -1-azon iabicyclo(2.2.2]octane; trifluoroacetate 3 (2-Hydroxy-2, 2-diLthien-3--ylacetoxy) (3-phenoxypropyl) -1-azoni abicycio[2.2.2loctane; bromide 1- (3-phenylallyl) -(9-Hydroxy-9 -fluorene-9-carbonyloxy) -l-azo niabicyclo[2.2.2)octane; bromide 3 (9-Hydroxy-9 -filuorene-9-carbonyloxy) (3-phenoxypropyl) -1-a zoniabicyclo[2.2.2]octane; bromide 3R-(9-Hydroxy-9[(H)-f luorene-9-carbonylox) -1-phenethyl--azoniabic yclo[2.2.2]octane; bromide (9-Hydroxy-9H-fluorene-9-carbonyloxy)-1 -(3-thien-2-ylpropyl)-1azoniabicyclo[2.2.2]octane; bromide 3 -Me thy! -9 [H I-flubrene-9-carbonyloxy) 3-phelylallyl) -1-a zoli a 00 bicyclo[2.2.2]octane; bromide 3 (9 -Me thyl-9 -fluorene-9-carbonyloxy) (3-phenoxypropyl) -1 -a zo niabicyclo[2.2.2]octane; bromide I- (4-Phenylbutyl) -3 -xanthene-9-carbonyloxy) azoniabicyclo [2.2.2]octane; bromide l-(2-PhenoxyethyJ.)-3(R)-(9[H]-xanthefle-9-carbonyloxy)-l-azoniabicyclo [2.2.2]octane; bromide ri -(3-Phenoxypropyl)-3(R,)-(9[H]-xanthene-9-Carbolyloxy)-l-azofliabicyclo [2.2.2]octane; bromide l-Phenethyl-3 (9 -xanthene-9-carbonyloxy) -1-azoniabicyclo 2.2] octane; bromide 3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-l-(3-phe'oxypropyl)-lazoniabicyclo[2.2.2]octane; bromide 3 (9-Hydroxy-9 -xanthene-9-carbonyloxy) -l-phenethyl-1-azoniabicy dco octane; bromide 3 (9-H-ydroxy-9H-xanthene-9-carbonyloxy) (3-thien-2-ylpropyl) -1azoniabicyclo[2.2.2]octane; bromide 3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-l-(3-pheloxy-propyl)-l-a zonia-bicyclot2.2.2]octane; bromide The present invention also provides processes for preparing compounds of formula The quaternary ammonium derivatives of general Formula I, may be prepared by reaction of an alkylating agent of general Formula II with compounds of general Formula III. in Formulas I, II and III, R 1
R
2 p,3, A, X, B, n, m and p are as defined above.
o B R1 C (CH2n -A
(CH
2 )m -X
N-(CH)
0 00 R2 R3 II Methods b) SR1 C (CH 2 -A 9 O R2 R3 X
I
This alkylation reaction may be carried out by .two different experimental procedures, a) and b)which are described below. In particular method b) provides a new experimental process, using solid phase extraction methodologies, that allows the parallel preparation of several compounds. Methods a) and b) are described in the experimental section. Compounds of general Formula II which are not commercially available have been prepared by synthesis according to standard methods. For example, compounds wherein n 0 and A= or -NR 6 wherein R 6 is as defined above, were obtained by reaction of the corresponding aromatic derivative or its potassium salt with an alkylating agent of general formula wherein X may be a halogen and Y may be a halogen or a sulphonate ester. In other examples, compounds of general Formula II, where n>=l were synthesised from the corresponding alcohol derivative of general Formula IV by known methods.
R1 (CH 2 -A (CH 2 )m -OH R2 R3
IV
Compounds of general Formula III may be prepared by three 00 e- 11 different methods c,d and e illustrated in the following scheme and detailed in the experimental section.
OH
Method c N
V
B'
O--
O
B O 0, 0 Method d
OH
N- (CH) B CI V O o~ N
B
Method e
N
0,.
N- OH N )(CH)
V
Some compounds of general formula III where B is a group of formula R 8 and R 9 are as described above and R" is a hydroxy group, may also be prepared from the glyoxalate esters of general formula VII by reaction with the corresponding organometallic derivative.
0 ao) R8
N-(CH)
R9- [Mg,Li] 0 B M (CH) 0 Method f Compounds of general formula VII may be prepared from the corresponding glyoxylic acids following the standard methods c, d and e described above and detailed in the experimental section. The glyoxalate derivatives of formula VII where R 8 is a 2-thienyl or 2furyl group have not been described before.
The following compounds are examples of compounds of general formula III and VII which have not been described before: 9-Methyl-9[H]-fluorene-9-carboxylic acid l-azabicyclo[2.2.2]oct-3(R) 0D 12
CN
-yl ester (intermediate I-1c); 9-Methyl-9[H]-xanthene-9-carboxylic acid l-azabicyclo[2.2.2]oct-3(R) OO -yl ester (intermediate I-1d); 2-Hydroxydithien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester (intermediate I-4a).
Oxothien-2-yl-acetic acid l-azabicyclo[2.2.2]oct- 4 -yl ester C( (intermediate I-4b).
S Oxothien-2-yl-acetic acid l-azabicyclo[.2.2.2]oct-3(R)-yl ester S (intermediate I-4g).
Oxofuran-2-yl-acetic acid l-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e).
2-Hydroxy-2,2-difuran-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-3(R) -yl ester (intermediate I-4d).
Compounds of Formula V could be: 4-hydroxy-l-azabicyclo[2.2.1]heptane, described in W0150080 4-hydroxy-l-azabicyclo[2.2.2]octane, described in Grob, C.A. et.al.
Helv.Chim.Acta (1958), 41, 1184-1190 3(R)-hydroxy-l-azabicyclo[2.2.2]octane or 3(S)-hydroxy-1azabicyclo[2.2.2]octane, described in Ringdahl, R. Acta Pharm Suec.
(1979), 16, 281-283 and commercially available from CU Chemie Uetikon GmbH.
The following examples are intended to illustrate, but not to limit, the experimental procedures that have been described above.
The structures of the prepared compounds were confirmed by 1
H-
NMR and MS. The NMR were recorded using a Varian 300 MHz instrument and chemical shifts are expressed as parts per million from the internal reference tetramethyl silane. Their purity was determined by HPLC,. using reverse phase chromatrography on a Waters instrument, with values greater than 95% being obtained. Molecular ions were obtained by electrospray ionization mass spectometry on a Hewlett Packard instrument.
Method a Example 20- Preparation of 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenyl acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane, bromide.
1 200. mg of Furan-2-yl)-hydroxy-phenylacetic acid 1-aza-bicyclo[2.2.2] 00 oct-3(R)-yl ester (0.6 mmol) were suspended in 4 ml of CH3CN and 6 ml of CHC13. To this suspension were added 0.48 ml (3 mmol) of 3phenoxypropyl bromide. After stirring for 72 h at room temperature in inert atmosphere, solvents were evaporated. Ether was added and the S mixture stirred The solid obtained was filtered and washed several C( times with ether. The yield was 0.27 g of title compound as a S mixture of diastereomers.
NMR (DMSO-d6): 6 1.50-2.20 6H), 2.25 1H), 3.10 (m,1H), 3.20-3.60 6H), 3.95 1H), 4.05 2H), 5.20 1H), 6.25-6.35 (double dd, 1H), 6.45 1H), 6.95 4H), 7.30-7.50 7H), 7.7.0 1H); MS 462; mp 166 0
C.
Method b Example 51 Preparation of 3(R)-(2-Hydroxy-2,2-di-thien-2-yl acetoxy)-1-[3-(naphthalen- l-yloxy)propyl]-1-azoniabicyclo[2.2.2] octane; trifluoroacetate 60 mg (0.17 mmols) of hydroxy-dithien-2-yl-acetic acid 1-aza-bicyclo[2.2.2]oct-3(R)-yl ester were dissolved in 1ml of dmso.
To this solution 188 mg (0.85 mmol) of 3-(naphthalen-1-yloxy)- propyl chloride were added. After stirring overnight at room temperature, the mixture was purified by solid phase extraction with a cation exchange Mega Bond Elut cartridge, previously conditioned at pH 7.5 with 0.1 M NaH2PO4 buffer. The reaction mixture was applied to the cartridge and washed first with 2 ml of DMSO and then three times with 5 ml of CH3CN, rinsing away all starting materials. The ammonium derivative was eluted with 5 ml of 0.03 M TFA solution in CH3CN:CHC13 This solution was neutralized with 300 mg of poly(4-vinylpyridine), filtered and evaporated to dryness.
The yield was 17 mg of title compound. 1 H- NMR (DMSO-d6): 5 1.7 2.1 4H), 2.2 2-.4 3H), 3.2 3.6 7H), 4.0 1H), 4.2 2H), 5.25 1H), 7.0 (m 3H), 7.2 2H), 7.4 7.6 (m, 7H), 7.85 1H), 8.2 1H); MS [M-CF3COO]': 534.
I
Method c- 00 Methyl ester derivatives of general Formula VI were prepared by standard methods of esterification from the corresponding carboxylic acid or following the procedures described in examples I-le, I-if and S I-g or according to procedures described in literature: FR 2012964; Cr Larsson. L et al. Acta Pharm. Suec. (1974), 11(3), 304-308; Nyberg, K.
Cq et.al. Acta Chem.Scand. (1970), 24, 1590-1596; and Cohen, V.I. et.al.
S J.Pharm.Sciences (1992), 81, 326-329.
Example I-la- Preparation of (Furan-2-yl)hydroxyphenylacetic acid 1azabicyclo[2.2.2]oct-3(R)-yl ester.
3.24 g (0.014 mols) of (Furan-2-yl)-hydroxy-phenylacetic acid methyl ester were dissolved in 85 ml of toluene. To this solution were added 2.08 g (0.016 mols) of 3-(R)-hydroxy-l-azabicyclo[2.2.2]octane and 0.224 g (5.6 mmols) of HNa (60% dispersion in mineral oil). The mixture was refluxed with continuous removal of distillate and when necessary replacement with fresh toluene for 1.5 hours. The cooled mixture was extracted with 2N HC1 acid, the aqueous layer washed with ethyl acetate, basified with K2C03 and extracted with CHC13. The organic layer was dried over Na2SO4 and evaporated. The oil obtained (3.47 g) crystallised after cooling at room temperature. This solid was suspended in hexane and filtered. The yield was 2.5 g of a mixture of diasteroisomers, mp: 140-142 °C;GC/MS 327; NMR (CDC13) 1.20-1.70 4H), 1.90-2.10 1H), 2.45-2.80 (m, 3.10-3.30 1H), 4.8 (bs, OH), 4.90-5.0 1H), 6.20 1H), 6.35 1H), 7.30-7.50 4H), 7.60-7.70 2H).
After four crystallizations of 0.5 g of this mixture from boiling acetonitrile, 0.110 g of a pure diastereomer(1) were obtained.
From the mother liquors of crystallization was obtained the other diastereomer (*:configuration not assigned). Diastereomer 1 was hydrolysed to yield (+)-2-hydroxy-2-phenyl-2-furan-2-ylacetic acid as a pure enantiomer, [a] 25 +5.6 EtOH) Diastereomer 2 was hydrolysed to yield (-)-2-hydroxy-2-phenyl-2-furan-2-ylacetic acid as a pure enantiomer, 2 -5.7 c=2, EtOH).
Diastereomer 1: 2(*)(Furan- 2 yl) hydroxyphelyl acetic acid 1-azabi Scyclo[2.2.2]oct-3(R)-yl ester.'H- NMR (CDC13) 5 1.20-1.70 (mn, 4H), 00 1.90 2.45-2.50 (mn, 1H), 2.50-2.80 (in, 4H), 3.10-3.20 (mn, 1H), 4.8 (bs, OH), 4.90-5.0 (in, 1H), 6.20 (in, 1H), 6.35 (in, 1H), 7.30-7.50 (mn, 4H), 7.60-7.70 (in, 2H).
Diastereomer 2: 2(*)-(Furan-2-yl)hydroxyphenylacetic acid 1-azabi C1cyclo[2.2.2]oct-3(R)-yl ester. 1 H- NMR (CDC13): 5 1.20-1.70 (in, 4H), C1 2.10 (in, 1H), 2.50-2.80 (mn, 5K), 3.20-3.30 (in, 1H), 4.8 (bs, OK), 4.90- (mn, 1H), 6.20 (in, 1K), 6.35 (in, 1K), 7.30-7.50 (in, 4H), 7.60-7.70 (in, 2H).
Example I-lb- Preparation of Furan-2-ylhydroxythien-2-ylacetic acid l-azabicyclof2.2.2]oct-3 -yl ester.
Prepared as in example I-1 a. The yield was 3.06 g (64.3 of a mixture of dias tereoi some rs, inp: 17200; GO/MS 333; NMR (DMSO-d6) 5 1.21-1.27 (in, 1K), 1.41-1.60 (in, 3K), 1.87 (in, 1H), 2.36-2.69 (in, 5K), 3.02-3.14 (in, 1H), 4.75-4.82 (in, 1H), 6.24- 6.25 (in, 1K), 6.42-6.45 (in, 1K), 7.01-7.06 (in, 1H), 7.11-7.14 (in, 2K), 7.51-7.54 (mn, 1K) 7.66-7.69 (in, 1K).
Example I-ic- Preparatio n of 9-Methyl-9[H)-fluorefle-9-carboxylic acid 1-azabicycloE2 oct-3 -yl ester.
Prepared as in example 1- 1 a. T he yield was 3.34 g of an oil (80 This product 'was solidif ied by formation of the oxalate salt 1) ip: 18610. MS [M free base 334.
Oxalate salt 1 K- NMR (DMSO-d6) 5 1.43-1.55 (in, 2K), 1.68-1.78 (in, 2K), 1.75 3K), 2.02 (mn, 1H), 2.70-2.90 (mn, 1K), 2.92-3.15 (in 4K), 3.50-3.57 (in, 1K), 4.88 (mn, 1K), 7.35-7.47 (in, 4K), 7.62-7.70 (in, 2H), 7.89-7.91 2H).
Example I-id- Preparation of 9-Methyl-9[H)-xanthefle-9-carboxylic acid i-azabicyclot2.2.2]oct-3(R)-yl ester.
Prepared as in example 1- 1 a. The yield was 1.91 g of an oil This product was solidified by formation of the oxalate salt inp: 15200. MS [M free base 350.
kn 0 16
(N
Oxalate salt NMR (DMSO-d6): 6 1.20-1.30 1H), 1.40-1.52 (m, 1H), 1.64-1.81 2H), 1.90 3H), 2.0 1H), 2.53-2.66 1H), 00 2.71-2.76 1H), 2.97-3.10 3H), 3.44-3.52 1H), 4'.90-4.92 (m, 1H), 7.12-7.18 4H), 7.32-7.38 2H), 7.43-7.48 2H), 8.0-9.8 (bs, 1H, H') ci Example I-le-Preparation of 9-Methyl-9[H]-fluorene-9-carboxylic acid C-i methyl ester.
9 Lithium diisopropylamide (26.7 ml of a 2M solution in S heptane/tetrahydrofurane/ethylbenzene, 0.053 mol) was added to a stirred solution of 9[H]-fluorene-9-carboxylic acid (5 g 0.0237 molY) in THF (70 ml) at between 0 and 5°C in N, atmosphere. The mixture was warmed to room temperature and refluxed 1.5 hours. The reaction mixture was cooled to room temperature and a solution of CH3I (1.85 ml, 0.03 mol) in THF (1.85 ml) was added. The mixture was.stirred overnight at room temperature and evaporated. To the residue in MeOH (70 ml) was added concentrated sulfuric acid (3.9 ml) in MeOH (25 ml), the mixture was refluxed for 2 hours and evaporated. The residue was partitioned between chloroform and saturated K2CO3 solution. The aqueous layer was extracted again with chloroform and the organic layers were combined, washed with water, dried over sodium sulphate and evaporated to dryness to obtain 5.73 g of a brown oil. This product was purified by column chromatography (silica gel, hexane/ethyl acetate 95:5) to yield 4.43 g of a pure product structure confirmed by 1
H-NMR.
NMR (CDC13): 5 1.80 3H), 3.60 3H), 7.50-7.65 4H), 7.75 2H), 8.0 2H) Example I-if -Preparation of 9-Methyl-9[H]-xanthene-9-carboxylic acid methyl ester.
Prepared as in example I-le. The yield was 2.65 g 1 H- NMR (CDC13): 6 1.90 3H), 3.6 3H), 7.05-7.35 8H).
Example I-1g- Preparation of 9-Hydroxy-9[H]-xanthene-9-carboxylic acid methyl ester.
Lithium diisopropylamide (20.3 ml of a 2M solution in
I
S17 heptane/tetrahydrofurane/ethylbenzene, 0.041 mol) was added to a stirred solution of 7 g 0.029 mol) of 9[H]-xantene-9-carboxylic acid 00 methyl ester (prepared by a standard method) in THF (70 ml) at between 0 and 5 0 C in N 2 atmosphere. The mixture was stirred 1 h at this temperature and then was added by N2 pressure to a dry solution of S oxygen in ether at 0°C. After 30 min, an equal volum of NaHSO3 C1 aqueous solution, was added, and the reaction mixture was warmed to eCq room temperature and stirred for 30 min. The two layers were separated S and the aqueous phase was extracted twice with ethyl acetate. The C- organic phases were combined, treated with NaHSO3 (40% aqueous solution), washed with water, dried over sodium sulphate and evaporated to dryness to obtain 8.89 g of a brown solid.
This procedure was repeated with 5 g of starting material yielding 6.04g of the same brown solid.
The products were combined and purified by column chromatography (silica gel, hexane/ethyl acetate 90:10) to yield 7.60g (global Rt: of a pure product structure confirmed by 'H-NMR.
NMR (DMSO-d6): 5 3.5 3H), 7.0 1H, OH), 7.2 4H), 7.4 (m, 2H), 7.55 2H) Method d Example I-2a- Preparation of 10,11-Dihydro-5[H]-dibenzo[a,d] acid 1-azabicyclo[2.2.2]oct-3-(R)-yl ester.
2.15g of 10,ll-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic acid mmol) were dissolved in 40 ml of CHC13 (ethanol free). The solution was cooled at 0 OC and 0.86 ml of oxalyl chloride (9.9 mmols) and a drop of DMF were added. The mixture was stirred and allowed warm to room temperature. After an hour at this temperature the solvents were evaporated and the residue was dissolved in CHC13 and evaporated again. This procedure was repeated two times. The obtained oil was dissolved in 20 ml of toluene and added to a solution of 1.26 g (9.9 mmol) of 3-(R)-hydroxy-l-azabicyclo[2.2.2]octane in 40 ml of hot toluene. The reaction mixture was refluxed for 2 hours. After cooling the mixture was extracted with 2N HCI acid. The aqueous layer was basified with K2003 and extracted with CHCl3. The organic layer was Sdried over Na2SO4 and evaporated to dryness. The residue was purified 00 by column chromatography (silica gel, CHCl3:MeOH:NH4OH, 95:5:0.5) The *yield was 1.5 g (48 mp: 112-113 00; CG/MS 347; NMP.
(CDCl3) 1. 10-1. 35 (in, 2H) 1. 40-1. 52 (mn, 1H) 1. 52-1. 68 1H), 1 .90 (mn, 1H) 2 .40-2 .60 (in, 2H) 2 .60-2 .77 (mn, 3H) 2. 83-2 .96 (mn, 2H) c=I3. 07-3 .19 1H) 3. 25-3.40 (in, 2H) 4 .80 2H) 7.10-7. 30 8H).
10,11-Dihydro-5[H]-dibenzo[a,dlcycloheptane-5-carboxylic acid was prepared as described in Kuinazawa T. et al., J. Med. Chein.,.(1994), c~1 37, 804-810.
Example I -2b- Preparation of 5 -Dibenzo d] acid l-azabicyclo[2.2.2]oct-3-(R)-yl ester.
Prepared as in example I.-2a. The yield was 3.12 g mp 1290C; MS [M+1 346; NMR (DMSO-d6) 5 0. 90-1. 10 (mn, 2H) 1. 30-1. 50 (in, 2H), 1.58 (in, 1H), 2.21-2.26 (mn, 2H), 2.47-2.50 (in, 3H), 2.86-2.94 (in, 1H), 4.48-4.51 (in, 1H), 5.33 1H), 7.0 (in, 2H), 7.29-7.43 6H), 7.49-' 7.51 (mn, 2H).
acid was prepared as described in M.A. Davis et al; J. Med. Chein., (1964), Vol 7, 88-94.
Example I-2c-Preparation of 9, lO-Dihydroanthracene-9-carboxylic acid 1-azabicyclo oct-3- ester Prepared as in example I-2a. The yield was 0.77 g mp 13900; MS 334; NMR (DMSO-d6) 5 1.1-1.2 (in, lH) 1.25-1.40 (m, 2H) 1. 40-1. 55 (in, 1H) 1. 73 (in, 1H) 2. 20 (in, 1H) 2. 35-2. 65 (mn, 4H) 2. 90-2 .98 (mn, 1H) 3. 93-4.14 (dd, 2H, J 1. 8 Hz, J 4. 3 Hz) 4.56 (mn, 1H) 5.14 Cs, 7.25-7.35 (in, 4H) 7.35-7.50 4H).
9,10-Dihydro-anthracene-9-carboxylic acid was prepared as described in E. L. May and E. Mossettig; J. Am. Chem. Soc. (1948) Vol 70, 1077-9.
Method e- 1-3. Preparation of 2,2-Diphenylpropionic acid 1-azabicyclo [2.2.2]oct-3(R)-yl ester.
1.1 g (4.8 mmol) of 2,2-diphenylpropionic acid were dissolved in 00 ml of THF. To this solution were added 0.87 g (5.3 mmol) of 1,1'carbonyldiimidazole and the mixture was refluxed for an hour. 'The reaction was monitored by TLC following the formation of the imidazolide. When the reaction was completed part of the solvent was CA evaporated and 0.67 g (5.3 mmol) of 3 -(R)-hydroxy-1- CA azabicyclo[2.2.2] octane were added. The reaction mixture was refluxed S for 16 h, cooled,- diluted with ether and washed with water. The organic S layer was extracted with HC1 2N, the acid solution basified with K2CO3 and extracted with CHC13. The organic solution was dried over Na2SO4 and evaporated to dryness to yield 1.21 g of an oil that was identified as the title ester.
0.64 g (1.9 mmol) of 2,2-Diphenylpropionic acid 1-azabicyclo [2.2..2]oct-3(R)-yl ester were dissolved in 6 ml of ketone and 0.085.g( 0.95 mmol) of oxalic acid were added. After slow addition of ether a white solid was formed. The yield was 0.33g of oxalate of 2,2-Diphenyl-propionic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester; mp: 1460C; MS [M free base+l]*: 336.
Oxalate salt, NMR (CDC13): 5 1.40-1.64 2H), 1.90 3H), 1.80-2.0 2H), 2.31 2.73-2.85 1H), 3.0-3.10 1H), 3.10-3.32 3H), 3.53-3.70 1H), 5.13 1H), 7.14-7.40 9.25 (broad band, 2H, Method -f- Example I-4a- Preparation of 2-Hydroxy-2,2-dithien-2-ylacetic acid l-azabicyclo[2.2.2]oct-4-yl ester.
A solution of 2-thienylmagnesium bromide was prepared from 220 mg (9 mmols)of Magnesium and 0.86 ml (9 mmols) of 2-bromothiophene in 15 ml of THF. This solution was added to 1.95 g (7mmols) of oxothien-2-yl -acetic acid l-azabicyclo[2.2.2]oct-4-yl ester (intermediate I-4b) dissolved in 20 ml of THF. The mixture was stirred at room temperature for 1 hour, refluxed for 1 hour, cooled, treated with a saturated solution of ammonium chloride and extracted with ether. After removal of the solvent the solid obtained was recrystallised from acetonitrile to yield 1.45 g,of a white solid NMR (DMSO-d6): 5 1.80-2.0 00 6H), 2.80-3.0 6H), 7.0 2H), 7.13 2H), 7.18 1H), 7.51 2H); MS 350; mp 1740C.
Example I-4b- Preparation of oxothien-2-yl-acetic acid 1-azabicyclo S [2.2.2]oct-4-yl ester.
CA Oxalyl chloride (1.5ml, 0.017 mol) was added to a solution of oxothien- S 2-yl-acetic acid (2.24 g, 0,014 mol) and dimethylformamide (one drop) Cq in 30 ml of chloroform (etanol free) at 0°C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHC13 (30 ml) and added to a suspension of 1.lg (0,009mols) of 4-hydroxy-l-azabicyclo[2.2.2]octane, 1.8ml of triethylamine (0,013mols), 0.6g (0.9mmols) of N-(methylpolystyrene)-4-(methylamino) pyridine at 700C. The mixture was refluxed for 1 hour, cooled, filtered and washed with water. The title product was extracted with a solution of diluted HC1, washed with CHC13, basified with K2CO3 and extracted again with CHC13. After removal of the solvent 1.47g of a solid was obtained. NMR (dmso): 5 2.0 6H), 2.9 7.35 1H), 8.05 1H), 8.3 1H).
Example I-4c- Preparation of (Furan-2-yl)hydroxyphenylacetic acid 1azabicyclo[2.2.2]oct-3(R)-yl ester.
Phenylmagnesium bromide ,0.0057 mol (5.7 ml of a solution .M in THF), was added to a solution of 1.3 g 0.0052 mol) of oxofuran-2-ylacetic acid l-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e-) dissolved in 15 ml of THF, at -700C in N2 atmosphere. The mixture was stirred at this temperature for 10 minuts, and then warmed to room temperature After 1 hour the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate The organic phases were combined, washed with water and dried over Na2S04. After removal of the solvent, the solid obtained was treated with ether and filtered to yield 0.67 g (40 of a product whose structure was confirmed by 'H-NMR. This compound was also prepared as is described in Example I-la (Method c) The 00 diastereomers were separated by crystallization from acetonitrile and distinguished by 'H-NMR.
S Example I-4d- Preparation of 2-Hydroxy-2,2-difur-2-yl-acetic acid S 1-azabicyclo [2.2.2]oct-3(R)-yl ester.
C1 The title compound was synthesised as in example I-4c from intermediate S I-4e- and 2-furanyl lithium which was prepared whith furane and butyl C\ lithium following a standard method. The yield was 380 mg 1 H- NMR (CDC13): 6 1.2-1.4 1H), 1.4-1.8 3H), 2.0 1H), 2.6-2.85 (m, 3.2 1H), 5.0 1H), 6.4 3H), 7.3 1H), 7.5 2H) MS 318.
Example I-4e- Preparation of oxofuran-2-yl-acetic acid 1-azabicyclo [2.2.2]oct-3(R)-yl ester.
Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution of oxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (one drop) in 150 ml of chloroform (etanol free) at 0°C. The mixture was stirred and allowed to warm at room temperature. After five hours the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHC13 (150 ml) and a solution of 3(R)quinuclidinol (10.90 g, 0.086 mol) in CHC13 (150 ml) was added to this at 0°C. The mixture was stirred and allowed to warm at room temperature. After 15 h at the mixture was washed with aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 9.34 g of the title compound as a dark oil.
Estructure confirmed by NMR.
NMR (CDC13): 5 1.40-1.60 1H) 1.60-1.80 2H), 1.80-2.05 (m, 1H), 2.20 1H), 2.70-3.10 5H), 3.30-3.45 1H), 5.10 1H), 6.7 1H), 7.7 1H), 7.8 1H).
Example I-4f- Preparation of 2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid l-azabicyclo[2.2.2]oct-3(R)-yl ester.
I
The title compound was prepared as described in example I-4c from intermediate I-4g. The. yield was 3 g as a mixture of 00 diastereomers. After five crystallizations of 1.5 g of this mixture from boiling isopropanol, 0.200 g of a pure diastereomer(1) were obtained. The mother liquors from first crystallization were enriched with the other diastereomer Diastereomer 1 was hidrolysed to CA yield (+)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid as a pure Cr enantiomer 25 +25.4 EtOH). This value was assigned to the S R configuration provided that in literature (A.I.Meyers et.al.
J.Org.Chem. (1980),45(14), 2913) the 2(S) enantiomer has been described whith 20 EtOH).
Diastereomer 1: 2 -2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid 1-aza bicyclo[2.2.2]oct-3(R)-yl ester. 1H-NMR (DMSO-d6): 5 1.1-1.25 1H) 1.3-1.6 3H), 1.83 1H), 2.4-2.7 5H), 3.1 1H), 4.8 (m, 1H), 7.0 2H), 7.05 1H), 7.3-7.4 3H), 7.4-7.45 2H), 1H).
Diastereomer 2: 2(S)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid 1-aza bicyclo[2.2.2]oct-3(R)-yl ester.H-NMR (DMSO-d6): 5 1.1-1.25 1H), 1.4-1.6 3H), 1.9 1H), 2.3-2.7 5H), 3.05 1H), 4.8 (m, 1H), 7.0 2H), 7.05 1H), 7.3-7.4 3H), 7.4-7.45 2H), 1H).
Example I-4g- Preparation of oxothien-2-yl-acetic acid 1-azabicyclo [2.2.2]oct-3(R)-yl ester.
Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution of oxothien-2-yl-acetic acid (2 g, 0,0128 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 0°C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHC13 (30 ml) and a solution of 3(R)quinuclidinol (1.95g, 0.0154 mol) in CHC13 (30 ml) was added to this at 0°C. The mixture was stirred and allowed to warm at room temperature. After 1.5 h at the mixture was washed with aqueous potassium carbonate, then with water, dried over Na2SO4 and 23 evaporated to give 3.14 g of the title compound as a yellow oil. H- NMR (CDC13): 5 1.40-1.50 1H), 1.50-1.70 1H), 1.70-1.80 00 1H), 1.90-2.0 1H), 2.15 1H), 2.70-3.05 5H), 3.30-3.40 1H), 5.05 1H), 7.20 1H), 7.85 1H), 8.10 1H).
SOther carboxylic acids of Formula B-C(O)OH, whose preparation C1 (or the syntheses of their derivatives methyl ester, chloride or C( imidazolide) haven't been described in methods c,d,e or in the S Examples I-le, I-if and I-1g, and that are not commercially available, could be prepared as is described in the following references: FR 2012964 M.A. Davis et al; J. Med. Chem. (1963), 6, 513-516.
T. Kumazawa et al; J.Med. Chem, (1994), 37(6), 804-810.
M.A. Davis et al; J. Med. Chem., (1964), Vol(7), 88-94.
Sestanj, K; Can. J. Chem., (1971), 49, 664-665.
Burtner, R. J. Am. Chem. Soc., (1943), 65, 1582-1585 Heacock R.A. et al; Ann. Appl. Biol., (1958), 46(3), 352-365.
Rigaudy J. et.al; Bull. Soc. Chim. France, (1959), 638-43.
Ueda I. et al; Bull. Chem. Soc. Jpn; (1975), 48 2306-2309.
E.L. May et.al.; J. Am. Chem. Soc., (1948), 70, 1077-9.
Also included within the scope of the present invention are pharmaceutical composition which comprise, as the active ingredient, at least one quinuclidine derivative of general formula in association with a pharmaceutically -acceptable carrier or diluent.
Preferably the composition is made up in a form suitable for oral administration.
The pharmaceutically acceptable carrier.or diluents which are mixed with the active compound or compounds, to form the composition of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administration of the composition.
Compositions of this invention are preferably adapted for oral administration. In this case, the composition for oral administration may take the form of tablets, film-coated tablets, liquid inhalant, powder inhalant and inhalation.aerosol; all containing one or more compounds of the invention; such preparations may be made by methods well-known in the art.
00 The diluents which may be. used in the preparations of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or film-coated tablets may CA conveniently contain between 500 and 1 mg, preferably from 5 to 300 mg C1 of active ingredient. The inhalant compositions may contain between 1 S pg and 1,000 g,.preferably from 10 to 800 pg of active ingredient.In S human therapy, the dose of the compound of general formula depend on the desired effect and duration of treatment; adult doses are generally between 3 mg and 300 mg per day as tablets and 10 ug and 800 tg per day as inhalant composition.
Pharmacological Action The following examples demonstrate the excellent pharmacological activities of the compounds of the present invention. The results on human muscarinic receptors binding and in the test on bronchospasm in guinea pig, were obtained as described below.
Human muscarinic receptor studies.
The binding of 3 H]-NMS to human muscarinic receptors was performed according to Waelbroek et al (1990) Assays were carried out at 25°C. Membrane preparations from stably transfected chinese hamster ovary-Kl cells (CHO) expressing the genes for the human muscarinic receptors Hm3 were used.
For determination of IC,, membrane preparations were suspended in DPBS to a final concentration of 89 pg/ml for the Hm3 subtype. The membrane suspension was incubated with the tritiated compound for min. After incubation the membrane fraction was separated by filtration and the bound radioactivity determined. Non specific binding was determined by addition of 10' M atropine. At least six concentrations were assayed in duplicate to generate individual displacement curves.
00 COMPOUNDS BINDING TO RECEPTOR No M 3
(IC
50 nM) ATROPINE 3.2 IPR.ATROPIUM 1 31 2 7 22 8 4.8 17 14 18 6.6 6.8 .13 36 2.7 39 3.8 44 4. 4 53 5. 6 71 8.2 74 16 77 3.1 78 84 9. 9 89 5.4 99 31 100 14 r oo o
OO
101 7.6 109 31 114, 14 116 23 126 13 127 16 128 8.8 129 6.3 136 11 137 6.9 138 19 146 13 M. Waelbroek, M. Tastenoy, J. Camus, J Christophe. Binding of selective antagonists to four muscarinic receptors (Ml to M4) in rat forebrain. Mol. Pharmacol. (1990) 38: 267-273.
Our results show that the compounds of the present invention have affinities for the M 3 receptors which are very similar to the reference compounds.
The compounds of the invention preferably have high affinities for muscarinic M 3 receptors (HM3), preferably human muscarinic receptors. Affinity levels can typically be measured by in vitro assays, for example, as described above.
Preferred compounds of the invention have an ICso (nM) value for
M
3 receptors of less than 35, preferably less than 25,20 or 15, more preferably less than 10,8 or Test on bronchospasm in guinea pig The studies were performed according to Konzett and Rossler Aqueous solutions of the agents to be tested were nebulized and inhaled 0 27 by anaesthetized ventilated male guinea pigs (Dunkin-Hartley). The bronchial response to intravenous acetylcholine challenge was 00 determined before and after drug administration and the percent change in pulmonary resistance at several time-points.
2. Konzett Rossler F. Versuchsanordnung zu Untersuchungen ander bronchialmuskulatur. Arch. Exp. Path. Pharmacol. 195: 71-74 (1940) (C The compounds of the present invention inhibited the bronchospasm (C response to acetylcholine with high potency and a long duration of S action.
C<1 From the above described results one of ordinary skill in the art can readily understand that the compounds of the present invention have excellent antimuscarinic activity (M 3 and thus are useful for the treatment of diseases in which the muscarinic M 3 receptor is implicated, including respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis, urinary diseases such as urinary incontinence and pollakinuria in neuripenia pollakinuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystitis and gastrointestinal diseases such as irritable bowel syndrome, spastic colitis and diverticulitis.
The present invention further provides a compound of formula (I) or a pharmaceutically acceptable composition comprising a compound of formula(I) for use in a method of treatment of the human or animal body by therapy, in particular for the treatment of respiratory, urinary or gastrointestinal disease.
The present invention further provides the use of a compound of formula or a pharmaceutically acceptable composition comprising a compound of formula for the manufacture of a medicament for. the treatment of respiratory, urinary or gastrointestinal disease.
Further, the compounds of formula and pharmaceutical compositions comprising a compound of formula can be used in a method of treating respiratory, urinary or gastrointestinal disease, which method comprises administering, to a human or animal patient in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula The present invention will be further illustrated by the following examples. The examples are given by way of illustration only S and are not to be construed as limiting.
00 Example 1 3 -DiphenyJlacetoxy-l- (3-phenoxypropyl) -1-azoniabicyclo [2 octane; bromide C1 The title compound was synthesised according to methods d and a. The yield of final step was 500 mg 81%. NMR (CDCl,) 1. 72-2. 18 (mn, 6H), 2.35 (mn, 1H), 3.0 (in, 1H), 3.23 (in, 1H), 3.59-3.88(m, 5H), (in, 2H), 4.30 Cm, lH), 5.1 1H), 5.25 (in, lH), 6.8-6.9 (in, 2H), 6.9-7. 0 (mn, lH) 7.2-7.4 12H) MS [M-Br) 456; mp 129 00.
Example 2 3 CR) -(2-Hydroxy-2 ,2-diphenylacetoxy) -1-(3-phenoxypropyl) -1-azoniabic yclo[2.2.2]octane; bromide The title compound was synthesised according to methods c and a. Th~e yield of final step was 280 mng NMR (DMSO-d6): 5 1.5S 1.7 Cm, 2H), 1.9 2.1 4H), 2.3 (mn, 1H), 3. 1 (in, 1H), 3.2 (in, 6H), 3.9 4.1 (in, 3H), 5.25 (in, 1H), 6.8 (bs, OH), 6.95 Cm, 3H), '7.2 7.5 (in, 12H) MS 472; mp 19900.
Example 3 3(R) -t2 ,2-Bis (4-fluorophenyl) -2-hydroxyacetoxy (3-phenoxypropyl) l1-azoniabicycloE2 octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 400 mg NMR (DMSO-d6) 5 1. 5-1. 65 (in, 1H), 1.7-1.8 (in, lH), 1.85-2.0 Cm, 2H), 2.05-2.2 (in, 2H), 2.3 1H), 3.1-3.2 Cm, 1H), 3.3-3.5 (m 3.95 Cm, 1H), 4.05 (in, 5.25 Cm, 1H), 6.9-7.0 4H), 7.1-7.5 10H); MS 508; mp 25310.
Example 4 3 ,2-Bis (4-fluorophenyl) -2-hydroxyacetoxy] -l-phenethyl-1-azonia bicyclo octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 300 mng NMR (DMSO-d6) :5 1.5-1.65 Cm, 1H), 1.7-1.85 (mn, 1H), 1.85-2.1 (in, 2.3 (mn, 1H), 2.9-3.1 (mn, 2H), S3.15-3.25 (mn, 1H) 3. 3-3. 6 (mn, 6H) 3. 95-4.05. (mn, 1H) 5. 25 IH), 00 6.95 7 5 (in, 13H) MS [M-Br] 478; inp 182 0
C.
Example 3(R)-(2-Hydroxy-2,2-di-p-tolylacetoxy)-1-(3-phenoxypropyl)-l-azoiia CI bicyclo[2.2.21octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 500 mng NMR (DMSO-d6): C1(mn, 2H) 1. 85-2. 0 (mn, 2H) 2. 05-1. 15 (mn, 2H) 2.3 7H) 3. 05-3.15 (mn, 1H), 3.25-3.5 (mn, 3.95 (in, 1H), 4.05 2H), 5.2 (mn, 1H), 6. 8 OH-) 6. 95 (in, 3H) 7. 1-7. 2 (mn, 4H) 7. 2-7. 35 (mn, 6H) MS [M- Br]':500; mp 183'C.
Example 6 3 (2-Hydroxy-2 ,2-di-p-tolylacetoxy) -1-phenethyl-l-azoniabicyclo [2 octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 650 mng 1 K- NMR (DMSO-d6) 1.55-1.8 (in, 2H), 1.85-2.05 (mt, 2K), 2.25 7K), 2.9-3.05 (in, 2K), 3.1-3.25 (in, 3.3-3.55 (mn, 6H) 3.95 (mn, 1K) 5.25 (in, 1H), 6.8 OH), 7.1-7.2 (in, 4H), 7.2-7.35 (in, 9H); MS [M-Brl 4 :470; mp 144 0
C.
Example 7 3 (2,2-Diphenylpropionyloxy) (3-phenoxypropyl) -l-azoniabicyclo [2.2.2]octane; bromide The title compound was synthesised according to methods e and a. The yield of final step was 250 mng 61%. NMR (CDC1 3 5 1.47-1.60 (in, 1K), 1.8-2.0 (in, 1K), 2.0 3K,2.0-2.15 (in, 4K), 2.39 Cs, 1H), 2.6 (mn, 1K), 2.92 1K), 3.6 (mn, 1K), 3.7-3.9 (mn, 4K), 4.0 (mn, 2H) 4.3 (mn, 1H), 5.25 (mn, 1K), 6.85 (in, 2K), 7.0 (in, 1K), 7.3 (in, 12K); MS [M- BrP': 470; mp 186 'C.
Example 8 3(R) -(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy) -1-(3-phenoxypropyl) -1- S azoniabicyclo octane; bromide S The title compound was synthesised as a mixture of diastereomers 00 according to methods c and a. The yield of final step was 520 mng .62%.
H- NMR (DMSO-d6): 5 1.5 1.95 (mn, 4K), 2.1 (in, 2H), 2.3 Cm, 1H), 3.1 (in, 1H), 3.3 3.5(m, 6H), 3.9 1H), 4.05 Ct, 2H), 5.2 (mn, 1H), (in, 4H), 7.15 2H), 7.35 (in, 5H), 7.5 Cm, 3H); MS 478; cI mp 220'C.
Example 9 3 -(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy) 1-1- (3-phenoxypro pyl) -l-azoniabicyclo 2] octane; trifluoroacetate The title compound was synthesised according to methods f and b from intermediate I-4f,diastereomer 1. The yield of final step was 10 mng 23%. 1 K- NMR (DMSO-d6) 5 1.5-1.6 1H) 1. 65-1.75 (in, 1H) 1. 8-2. 0 1 m, 2K), 2.05-2.1 (mn, 2K), 2.3 (in, 1K), 3.05-3.2 1K), 3.25-3.55 6K), 3.85-3. 95 1H) 4 .0 2K) 5. 2 (in, 1K) 6. 95 3H) 7. 03 1H), 7.15 Cdd, 1H), 7.2 Cs, OK), 7.3-7.5 Cm, 5K), 7.45-7.55 (m, 3K); MS (M-CF3000P*: 478.
Example 3(R) -t2 -(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy) -1-(3-phenoxypro pyl) -l-azoniabicyclo[2 2Joctane; trifluoroacetate The title compound was synthesised according to methods f and b from intermediate I-4f,diastereomer 2. The yield of final step was 3 mg 11%.1 K- NMR (DMSO-d6): 5 1.6-1.75 2H) 1.8-2.0 m, 4K) 2.25 (m, 2.8 Ct, 2K), 2.95-3.1 1K), 3.15-3.5 (mn, 6K), 3.8-3.95 1K), 5.2 1K), 6.92 6.96-7.03 2K), 7.1 (dd, 1H), 7.18 (s, OK), 7.3-7.4 (mn, 4H), 7.43-7.5 2H), 7.51 (dd, 1K); MS (M-CF3CCOO]: 478.
Example 11 3 [2 (2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy) J (3-phenyiprop yl) -1-azoniabicyclo[2.2 .2]octane; trifluoroacetate The title compound was synthesised according to methods f and b from intermediate I-4f,diastereoiner 1. The yield of final step was 9 mg, 22%. K NMR (DMSO-d6) :5 1. 45-1. 55 (mn, 1K) 1. 65-1. 75 ,1K) *31 S 1.85-2.05 2H), 2.3 1H), 2.9-3.1(m, 2H), 3.1-3.25 1H), S 3.25-3.55 6H), 3.9-4.0 1H), 5.25 1H), 7.05 1H), 7.15 00 1H), 7.2 1H), 7.25-7.4 8H), 7.45 2H, 7.55 1H); MS [M-CF3COO]': 448.
Example 12 CI 3(R) [2 -(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy) (3-phenylprop C yl)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods f and b from S intermediate I-4f,diastereomer-1. The yield of final step was 11 mg 26%.1 H- NMR (DMSO-d6): 5 1.45-1.55 1H), 1.6-1.75 1H), 1.8-2.0 4H), 2.25 1H), 2.55 2H), 3.0-3.1 1H), 3.15-3.55 (m, 6H), 3.8-3.9 1H), 5.2 1H), 7.0 1H), 7.1 1H), 7.15-7.4 9H), 7.45 2H), 7.5 1H); MS [M-CF3COO]*: 462.
Example 13 3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy))-1-(2-thien-2-yl ethyl)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods f and b from intermediate I-4f,diastereomer 1. The yield of final step was 10 mg 24%. 1 H- NMR (DMSO-d6): 5 1.45-1.55 1H), 1.65-1.75 1H), 1.8-2.0 2H), 2.3 1H), 3.1-3.6 9H), 3.9-4.0 1H), 5.25 1H), 7.0 3H), 7.15 (dd, 1H), 7.2 OH), 7.3-7.4 3H), 7.45-7.55 MS [M-CF3CO00]*:454.
Example 14 3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-thien-2-yl propyl)-1-azoniabicyclo[2.2.2octane; trifluoroacetate The title compound was synthesised according to methods f and b from intermediate I-4f,diastereomer 1. The yield of final step was 8 mg 19%. 1 H- NMR (DMSO-d6): 5 1.45-1.6 1H), 1.65-1.75 1H), 1.8-2.05 4H), 2.25 1H), 2.8 2H), 3.0-3.15 1H), 3.2-3.5 6H), 3.8-3.95 1H), 5.2 1H), 6.92 6.96-7.03 (m,2H), 7.13 (dd, 1H), 7.2 OH), 7.3-7.4 4H), 7.45-7.5 2H), 7.52 (dd, 1H); MS [M-CF3COO]': 468.
Example 3(R) (S)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy) ]-1-(3-thien-2-y.
00 propyl) -1-azoniabicyclo[2.2 .2]octane; trifluoroacetate The title compound was synthesised according to methods f and b from intermediate I-4f,diastereomer 2. The yield of final step was 7 mg 26%.'1 H- NMR CDMSO-d6) 5 1.6-1.75 (in, 2H) 1.8-2.0 4H) 2.25 (in, 1H), 2.8 2H), 2.95-3.1 (in, 1H), 3.15-3.5 6H), 3.8-3.95 Cm, 1H), K1 5.2 (mn, 1H), 6.92 6.96-7.03 2H), 7.1 (dd, 1H), 7.18 (s, OH), 7.3-7.4 4H), 7.43-7.5 (in, 2H), 7.51 (dd, 1H); MS [M-CF3COJ: C1 468.
Example 16 3 [2 (2 -Hydroxy- 2-phenyl- 2- thien- 2-yl ace toxy) (2-phen oxyeth yl) -l-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods if and b from intermediate I-4f,diastereomer 1. The yield of final step was 11 mg 26%.1 H NMR (DMSO-d6): 5 1.5-1.6 (in, 1H), 1.65-1.75 1H), 1.8-2.0 (mn, 2H), 2.25 1H), 3.15-3.6 5K), 3.7 (in, 2H), 4.0 2H), 4.4 m,2H), 5.25 1K), 6.95-7.03 7.12 (dd, 1H), 7.2 Cs, OH), 7.3-7 .4 Cm, 5K), 7.4-7.5 Cm, 3H); MS [M-CF3000P*: 464.
Example 17 3(R) -(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy) -1-(3-phenylallyl) -1azoniabicyclo [2 octane; bromide The title compound was synthesised as a mixture of diastereoners according to methods c and The.yield of final step was 240 mg 77%.
'H-NMR (DMSO-d6) :5 1. 55-2. 0 Cm, 4H) 2. 27 Cm, 1H) 3. 05-3. 55 Cm, 5K) 3.88-3. 98 Cm, 1H) 4.0-4. 10 2K) 5. 21 (m,1H) 6. 23-6. 31 Cdoble dd, 1H), 6.36-6.48 Cm, 2K), 6.83-6.90 Cdd, 1H), 6.95 Cd, OH), 7.26-7.66 Cm, 1lK); MS 444; mp 9900.
Example 18 3 -(2-Furan-2-yl-2-hydroxy-2-pheiylacetoxy) -1-(2-phenoxyethyl) -1-a zorijabicyclo octane; bromide The title compound was synthesised as "a mixture of diastereomers according to methods c and a. The yield of final step 'Was 210 mg 66%.
H- NMR CDMSO-d6) 5 1. 50-2. 05 Cm, 4H) 2. 27 m, 1H) 3 .20 1 H), 00 3.37-3.65 (in, 4H), 3.65-3.75 (in, 2H), 4.04 (in, 1H), 4.40 (in, 2H), .2 1 Cm, I1H) 6. 2 3- 6.3 2 (dobl1e dd, 1lH) 6. 44 (in, 1H) 6.9 4 04 (in, 4 H) 7 .3 3 50 7H) 7. 64 1H) MS Br] 4 486; mp 16 300 Example 19 3(R) -(2-Furan-2-yl-2-hydroxy-2-phexylacetoxy) (2-phenoxyeth yl) -1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b from intermediate I-la, diastereomer 1. The yield of final step was 11 mg, 23%. H- NMPR (DMSO-d6) 5 1. 65-1. 80 2H) 1. 80-2. 10 2H), 2. 27 (in, lH), 3.15-3.65 Cm, 5H), 3.68 (in, 2H), 4.0 (in, 1H), 4.40 Ct, 2H), 5.20 (in, 1H) 6 .23 Cd, 1H) 6. 42 Cm, 1K) 6. 92-7. 04 4K) 7. 30-7. 38 5K) 7.44-7. 50 Cm, 2H) 7. 64 1H) MS [M-CF3000P 448.
Example 3 (2-Furan-2-yl-2-hydroxy-2-phenylacetoxy) (3-phenoxypropyl)*-1azoniabicyclo octane; bromide The title compound has been described in method Example 21 3 [2 (2-Furan-2-yl-2-hydroxy-2-phenylacetoxy) (3-phenoxy pro pyl) -1-azoniabicyclo[2.2.2].octane; bromide The title compound was synthesised according to methods c and a from intermediate I-la, diastereomer 1. The yield of final step was 1.15 g 99%. 1 K- NMR (DMSOD-d6) 5 1. 60-2. 20 (in, 6H) 2.25 1K), 3. Cm,lK), 3.20-3.60 Cm, 6K), 3.95 1H), 4.05 2H), 5.20 1H), 6.25 (dd, 1H), 6.45 lH), 6.95 4H), 7.30-7.50 Cm, 7K), 7.70 Cm, 1K); MS [M-Br)P: 462; inplS61C.
Example 22 3 [2 (2-Furan-2-yl-2-hydroxy-2-phenylacetoxy) 1 (3-phenoxy pro pyl) -l-azoniabicyclo[2 octane; trifluoroacetate The title compound was synthesised according to methods c and b from S intermediate I-la, diastereomer 2. The yield of final step was 10 Mgt 00 20%. NMR (DMSO-d6) 1. 50-2. 20 6H) 2 .25 1H) 3. (m,l1H) 3. 20-3. 60 Cm, 6H) 3. 95 (in, 1H) 4.05 (mn, 2H) 5.2.0 1H), 6. 35 (dd, 1H) 6.4 5 (in, 1H) 6. 95 (mn, 4H) 7 50 7H) 7. 70 (in, 1H) MS [M-CF3000]*: 4 62.
CI Example 23 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-l-phenethyl-1azcniabicyclo[2. 2.2] octane; trifluoroacetate The title compound was synthesised as a mixture of diastereoners according to methods c and b. The yield of final step was 12 mg, 13%.
NMR (DMSO-d6): 5 1.5 Cm, 1H), 1.7 (in, 1H), 1.9 2.05 2H), 2.3 (mn, 1H), 2.95 2H), 3.15 1H), 3.25 3.55 (in, 6H), 3.95 1H) 5. 25 (in, 6.3 Cd, 1H), 6.45 (mn, 1H), 6.95 Cd, 1H), 7.25 7.45 (in, 8H), 7.5 2H), 7.7 1H); MS [M-CF 3 COOI*: 432.
Example 24 3 -(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]J-l-phenethyl-1-azo niabicyclo(2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b from intermnediate I-la, diastereoiner 1. The yield of final step was 16 mng, 1 H- NMR (DMSO-d6) :5 65-1. 80 Cm, 2H) 1.90-2.05 2H), 2.3 1H), 2.95 2H), 3.15 Cm, 1H), 3.25 3.55 3.95 Cm, 1H), 5.25 Cm, 1H), 6.26 Cdd, 1H), 6.46 Cm, 1H), 6.95 Cs, 1H, OH), 7.25 7.45 Cm, 8H), 7.5 Cm, 2H), 7.7 Cm, 1H) MS (M-CF3COO]': 432.
Example 3()[()(-uan2y--yrx-2peyaeoy]-l-phenethyl-1-azo niabicyclo £2 octane; trifluoroacetate The title compound was synthesised according to methods c and b from intermediate I-la, diastereoiner 2. The yield of final step was 14 mg, H- NMR CDMSO-d6): 5 1.50-1.80 Cm, 2H), 1.90-2.05 (in, 2H), 2.3 CmIH), 2.95 (in, 2H), 3.15 Cm, 1H), 3.25 3.55 6H), 3.95 5.25 Cm, 1H), 6.32 (cid, 1H), 6.46 1H), 6.95 1H, S OH), 7. 25 7. 45 8 7.5 Cm, 2H), 7.7 1H) MS [M-CF300]*: 00 432.
Example 26 3 R. 2 Frn y hdoy pey c oy (3-phenylprop C1yl)-1-azoniabicyclo 2.2]octane; trifjluoroacetate C1The title compound was synthesised according to methods c and b from intermediate I-la, diastereomer 1. The yield of final step was 10 mg, C1 E NMR CDMSO-d6): 5 1.60-1.75.(m, 2H), 1.80-2.0 4H), 2.25 (in, 1H), 2.50-2.60 Cm, 2H), 3.0 (in, 3.10-3.50 6H), 3.83 (m, 1H), 5.17 (in, 1H), 6.25 IH), 6.45 1H), 6.95 1H), 7.20-7.40 Am, 8H), 7.46-7.48 2H), 7.66 Cm, 1H); MS [M-0F3000]*: 446.
Example 27 3 [2 ()-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy) (2-thien-2-yl ethyl) -1-azoniabicyclo octane; trifluoroacetate The title compound was synthesised according to methods c and b from intermediate I-la, diastereomer 1. The yield of final step was 9.mg, H- NMR CDMSO-d6): 5 1.65-1.80 Cm, 1.85-2.05 Cm, 2.30 (mn, 1H), 3.10-3.40 Cm, 3H), 3.40-3.60 6H), 3.95 Cm, 5.24 (m, 1H), 6.27 1H), 6.47 Cm, 1H), 6.96 Cs, 1H), 7.0-7.04 Cm 2H), 7.36-7.
48 Cm, 4H), 7.49-7.54.Cm, 2H), 7.70 MS [M-CF3COO]*: 438.
Example 28 3 -(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy) 1-1- (3-thien-2-yl propyl) -1-azoniabicyclo[2 .2 octane; trifluoroacetate The title compound was synthesised according to methods c and b from intermediate I-la, diastereomer 1. The yield of final step was 9 mg, NMR CIDMSO-dG): 5 1.60-1.7S Cm, 2H) 1.80-2.05 4H) 2.26 Cm, 1H), 2.81 Ct, 2H), 3.02 Cm, 1H), 3.10-3.45 Cm, 6H), *3.85 Cm, 1H), 5.18 1H), 6.25 Cd, 1H), 6.45 Cm, 1H), 6.90-7.0 7.32-7.42 Cm, 4H), 7.45-7.51 Cm, 2H), 7.66 1H); MS IM 452.
Example 29.
36 (2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy) -1-phenethyl-1- Sazoniabicyclo 2.2] octane; trifluoroacetate 00 The title compound was synthesised as a mixture of diastereomers according to methods c and b. The yield of final step was 18 mg, NMR (DMSO-d6): 1.65 -2.05 (in, 4H), 2.3 Cm, 1H), 3.0 (in, 2H), 3.15 3.6 7H), 3.95 (mn, 1H), 5.25 (in, 1H), 6.35 (dd, 1H), 6.45 (K m, 1H), 7.05 (mn, 1H), 7.2 (dd, 1H), 7.25 -7.5 (in, 6H), 7.55 (in, 1H), -7.65 1H); MS [M-CF 3 COO]': 438.
Example 3(R) -(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy) -1-(2-phenoxyeth-yl) -1-azoniabicyclo 2]octaie; trifluoroacetate The title compound was synthesised as a mixture of diastereoiners according. to methods c and b. The yield of final step was 22 mg, *23%.
NMR (DMSO-d6): 5 2.65 2.05 (mn, 4H), 2.3 (in, IH), 3.15 3.65 (inj 7H), 4.05 (in, 1H), 4.4 Cm, 5.15 1H), 6.35 (dd, 1H), 6.45 1H), 6.95 7.05 4H), 7.15 1H), 7.3 7.4 3H), (dd, 1H), 7.65 Cd, 1H); MS (M-CF 3 COO]*: 454.
Example 31 3(R) -(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy) -1-(4-oxo-4phenylbutyl) -1-azoniabicyclo [2 .2.2]octane; trifluoroacetate The title compound was synthesised as a mixture of diastereomers according to methods c and b. The yield of final step was 15.4 mg, NMR (DMSO-d6): 5 1.65 2.1 Cm, 6H), 7.05 7.55 3.95 lE), 5.1 1H), 6.35 Cdd, 1H), 6.5 1H), 7.05 1H), 7.15 Cm, 1H), 7.3 1H), 7.55 Cm, 3H), 7.7 (dd, 8.0 2H); MS [M-CF 3 000P': 480.
Example 32 1- (3-phenoxypropyl) -3 (2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy) -1-azoniabicyclo octane; bromide The title compound was synthesised as a mixture of diastereoners according to methods c and a. The yield of final step was 100 ing, 41%.
H- NMR (DMSO-d6) 5 1.65 2.05 Cm, MH), 2. 1 2. 0 Cm, 2H), 2 .3 Cm, 37 1H), 3.15 1H), 3.25 3.6 3.9 4.1 5.1 1H), 6.35 1H), 6.45 1H), 6.95 3H), 7.05 1H), 7.2 (d, 00 1H), 7.3 3H), 7.55 1H), 7.7 1H); MS 520; mp 1730C.
Example 33 CI I- (3-phenoxypropyl)-3(R)-(2,2-difuran-2-yl-2-hydroxy C1 acetoxy)-l-azoniabicyclo[2.2.2]octane; bromide S The title compound was synthesised according to methods f and a. The CA yield of final step was 200 mg, 60%. NMR (DMSO-d6): 5 1.6-2'.20 (m, 6H), 2.3 1H), 2.95-3.65 7H), 3.80-4.10 3H), 5.2 1H), 6.3-6.6 4H), 6.8-7.0 3H), 7.1 OH), 7.3 2H), 7.7 (m, 2H); MS 452.
Example 34 3(R)-(2,2-Dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo [2.2.2]octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 240 mg 60%. NMR DMSO-d6): 5 1.85-2.10 4H), 2.30 1H), 3.40 1H), 3.44-3.80 6H), 4.10 1H), 4.45 2H), 5.20 1H), 5.90 1H), 6.95-7.05 5H), 7.05-7.15 2H), 7.30-7.40 2H), 7.45 2H); MS 454; mp 98°C.
Example 3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-l-azoniabicyclo [2.2.2]octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 280 mg 83%. NMR (DMSO-d6): 5 1.80-2.06 4H), 2.06-2.20' 2H), 2.20-2.30 1H), 3.20-3.65 (m,7H), 3.90-4.10 3H), 5.20 1H), 5.90 1H), 6.95-7.05 SH), 7.05-7.20 7.30-7.35 2H), 7.50 2H); MS 468; mp 148°C.
Example 36 3(R) (2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-l-azoniabicyclo [2.2.2]octane; bromide The title compound was synthesised according to methods c and a. The 00 yield of final step was 1 80 mg 59%. NMP. (DMSO-d6) 5 1.65 (4H, in), 2.35 1H), 3.0 Cm, 2H), 3.2 3.6 (in, 7H), 3.95 (mn, 1H), 5.25 Cm, 1H) 7.0 (in, 2H) 7.2 (in, 2H) 7.35 Cm, SH) 7.55 (mn, 3H); MS 454; mp, 21600.
CI Example 37 3 -(2-Hydroxy-2,2-dithien-2-ylacetoxy) -I-(3-phenylpropyl) -1-azonia CI bicyclo[2.2.21octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 450 mng 58%. NMR CCDC1 3 1.8 2.1 (m, 6H), 2.4 1H), 2.6 Cm, 2H), 3.4 3.8 (in, 7H), 4.2 1H), 5.25 1H), 6.1 Cbs, OH), 6.9 Cm, 2H), 7.1 7.3 Cm, 9H); MS 468; mp, 640C.
Example 38 3 -(2-Hydroxy-2 ,2-dithien-2-ylacetoxy) -1-(3-phenylallyl) -1-azonia bicyclo[2.2.21octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 260 mg 34%. NMR CCDC1 3 51.8 2.05 Cm, 4H), 2.4 Cm, 1H), 3.55 3.95 (in, 5H), 4.15 4.5 3H), 5.25 (mn, 11H), 5.9 OH), 6.15 Cm, 1h), 6.85 Ct, 1H), 6.9 7.05 3H), 7.15 (in, lH) 7.2 7.45 Cm, 7 H) MS 466; mp 124'C.
Example 39 3(R) -(2-Hydroxy-2 ,2-dithien-2-ylacetoxy) -1-(4-phenylbuty.) -1-azonia bicyclo [2.2 .22 octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 320 mng 40%. NMR CCDC13) 1. 6 2 .0 Cm, 8H), 2.4 Cm, 1H), 2.6 (mn, 2H), 3.4 -3.8 Cm, 7H), 4.2 Cm, 1H), 5.25 1H) 6. 05 Cbs, OH) 6. 95 Cm, 2H), 7.1 3 Cm, 9H-) MS [M-Br] 482; mp 640C.
Example S 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy) -1-(4-oxo-4-phenylbutyl) -1-a 00 zoniabicyclo [2.2 octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 16 mg 15%. NMR (DMSO-d6) 1.7 2.0 Cm, 6H), 2.15 Cm, 1H), 3.1 2H), 3.15 3.55 7H), 3.95(m, 1H), 5.25 Cm 1H) 7. 0 2 H) 7. 15 2 H) 7.55S (in, 5H) 7. 65 Ct, 18H), 8. 0 (d, 2H); MS [M-CF 3 000P: 4 96.
CI Example 41 3 -(2-Hydroxy-2 ,2-dithien-2-yJlacetoxy) -1-(3-phenylaminopropyl) -1-a zoniabicyclo [2 .2 octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 14 mg 14%. NMR C DMSO-d6): 6 1.7 Cm, 58), 2.3 C(m, 18), 3.0 3.5 Cm, 9H), 3.9 Cm, 18), 5.25 Cm, 1H), 5.65 Ct, 18), 6.55 Cm, 38), 7.0 Cd, 28), 7.1 Ct, 28), 7.15 Cm, 28), Cm, 3H); MS[M-CF 3 COO]*: 483.
Example 42 3 -(2-Hydroxy-2,2-.dithien-2-ylacetoxy) (methylphenylamino)pro pyl] -1-azoniabicyclo 2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of f inal step was 20 mg 19%. NMR CDMSO-d6) 5 1. 65 Cm, 6H), 2.9 Cs, 38), 3.1 Cm, 18), 3.2 3.45 Cm, 88), 3.95 Cm, 18), 5. 2 Cm, 18H), 6. 65 Ct, 18H), 6.75 Cd, 28), 7.0 Cm, 28), 7, 2 (in, 48), 7. 5 Cm, 38) MS [M-CF 3 COO] 4 97.
Example 43 3(R) -(2-Hydroxy-2,2-dithien-2-ylacetoxy) -1-(3-phenylsulfanyipropyl) l-azoniabicyclo[2.2.2] octane; bromide The title, compound was synthesised according to methods c and a. The yield of final step was 800 mg 83%. NMR CDMSO-d6) 1.6 -1.9 (in, 68), 2.3 (in, 18), 2.9S Ct, 28), 3.05 Cm, 18), 3.2 .3.5 Cm, 68), 3.9 C,18) 5.2 Cm, 18) 7. 0 (in, 28) 7.15 Cm, 28) 7.2 Cm, 18) 7. 35 (in, 48), 7. 5 (in, 28) MS 500.
Example 44 S 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-l- 00 azoniabicyclo[2.2.2] octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 4 90 mg, 9b% 'H NMR (DMSO-d6) :5 1. 7 (in, 2H) 1.95 (mn, 2H), 2.1 (in, 2H), 2.3 (in, 1H), 3.2 (in, 1K), 3.45 (in, 6H), (mn, 3H) 5. 15 (in, 1H) 6. 9 (in, 3 H) 7 .0 (mn, 2H), 7.2 7.3 (t, CN12H), 7.5 (in, 3H); MS EM-Br]*: 484; mp 227'C.
Cl Example 3(R) -(2-Hydroxy-2 ,2-dithien-2-ylacetoxy) -1-(3-o-tolyloxypropyl) -1azoniabicyclo[2.2.2] octane; trifluoroacetate The title compound was synthesised according to methods c a nd b The yield of final step was 19 mg 18%. 'K-NMR (DMSO-d6) :5 1.7- 2.0 4H) 2.1 2.2 (mn, 5H) 2.3 (in, 1H) 3.15 3. 5 (in, 7H) 3.9 4. 05 (in, 3H), 5.05 (mn, 1H), 6.85 1H), 6.9 1H), 7.0 2H), 7.15 (in, 4H), 7.5 3H); MS (M-CF 3 COO]': 498.
Exam ple 46 3(R)-(2-Hydroxy-2,2-dithien.-2-ylacetoxy)-1-[3-(2,4,6-trinethylphenox y)propyll -l-azoniabicyclo[2 .2.2]octane; trifluoroacetate The title compound was synthesised according to..iethods c and b. The yield of final step was 22 mg 20%. NMR DMSO-d6) :5 1. 7 (in, 2H), 1.95 (in, 2K), 2.1 (in, 2K), 2.2 9K), 2.35 3. 2 3. 5 .(in, 7K), 3.7 3.95 (in, 1K), 5.25 (in, 1K), 6.8 2K), 7.0 (in, 2H), 7. 2 (in, 2K) 7 .5 (mn, 3K) MS [M-CF3COO] 52 6.
Example 47 1- (2-tert-Butyl-6-methylphenoxy)propyl) -(2-hydroxy-2 ,2dithien-2-ylacetoxy) -1-azoniabicyclo[2 2] octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 18 mg 16%. NMR (DMSO-d6) :5 1. 3 9H), 2.7 (mn, 2H), 2.9 2H), 2.1 2KH), 2.2 3H), 2.3 (in, 1H), 3.2 3.5 (in, 3.8 2H), 3.95 (in, 1H), 5.2 (in, 1H), 6.9 7.15 (in, 7K), 7.5 (in, 3K); MS [M-CF3COOI*: 554.
41 Example 48 1-[3-(Biphenyl-4-yloxy)propyl)-3(R)-(2-hydroxy-2,2-dithien-2- 00 ylacetoxy) -1-azoniabicyclo[2.2.2]-octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 22 mg 19%. NMR (DMSO-d6): 5 1.7 2H), 1.9 2H), 2:15 2H), 2.3(m, 1H), 3.2 3.5Cm, 7H), 3.95(m, 1H), C1 4.1 2H), 5.25 1H), 7.0 4H), 7.2(m, 2H), 7.3(t, 1H), 7.45 cK 2H), 7.5 3H), 7.6 4H); MS [M-CF 3 COOI': 560.
Example 49 3(R) (2-Hydroxy-2 ,2-dithien-2-ylacetoxy) (5,6,7,8tetrahydronaphthalen-2-yloxy)-propyl -1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 23 mg 21%. NMR (DMSO-d6) 5 1.7 6H), 1.9 2.1 4H), 2.3 Cm, 1H), 2.65 4H), 3.15 3.5 7H), 3.95 2H), 5.25 1H), 6.65 2H), 6.95 1H), 7.0 2H), 7.2 2H), 7.5 3H); MS [M-CF 3 COO]*: 538.
Example 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(naphthalen-2-yloxy) propyl]-l-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised accordingto methods c and b. The yield of final step was 17 mg 15%. NMR CDMSO-dG): 5 1.7 2.0 Cm, 4H), 2.1 1H), 2.35 Cm, 1H), 3.15 3.35 7H), 3.95 1H), 4.17 2H), 5.25 1K), 7.0 Cm, 2H), 7.15 3H), 7.35 Cm, 2K), 7.5 Cm, 4H), 7.85 Cm, 3H); MS [M-CF 3 COO]': 534.
Example 51 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-l -[3-(naphthalen-1yloxy)propyl]-l-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound has been described in method Example 52 1-[3-(2-Chlorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetox 42 y)-1-azoniabicyclo [2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The 00 yield of final step was 20 mg 18%. NMR (DMSO-d6): 5 1.65 6H), 2.35 1H), 3.2 1H), 3.3 3.55 6H), 3.95 1H), 4.15 2H), 5.25 2H), 7.0 3H), 7.2 7.35 1H), 7.45 1H), 7.55 3H); MS [M-CFCOO]': 519.
Cl Example 53 1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2- C ylacetoxy)-l-azoniabicyclo [2.2.2]octane; chloride The title compound was synthesised according to methods c and a. The yield of final step was 180 mg 59%. NMR (DMSO-d6): 5 1.65 2.15 6H), 2.25 1H), 3.2 1H), 3.25 3.55 6H), 3.95 2H), 2H), 5.25 1H), 7.0 4H), 7.15 4H), 7.55 3H); MS 502; mp 160 OC.
Example 54 1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2ylacetoxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 14 mg 13%. NMR (DMSO-d6): 5 1.65 4H), 2.15 2H), 2.35 1H), 3.2 1H), 3.25 3.35 6H), 3.95 1H), 4.1 2H), 5.15 7.05 3H), 7.2 2H), 7.25 7.35 7.55 3H); MS [M-CF 3 COO]P: 520.
Example 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-trifluoromethyl phenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 19 mg 17%. NMR (DMSO-d6): 5 1.65 2.1 6H), 2.35 1H), 3.2 1H), 3.3 3.55 6H), 3.95 (m, 1H), 4.15 2H), 5.25 1H), 7.0 2H), 7.2 2H), 7.25 7.35 3H), 7.5 7.6 4H); MS [M-CF 3 COO]': 552.
Example 56 1-[3-(3-Cyanophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2- 00 ylacetoxy)-1-azoniabicyclo [2.2.2.]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 18 mg 17%. NMR (DMSO-d6): 5 1.65 2.1 6H), 2.35 1H), 3.2 1H), 3.3 -3.55 6H), 3.95 1H), 4.15 2H), 5.25 1H), 2H), 7, 18 2H), 7.3 (d, 1H), 7.45 2H), 7.55 4H); MS [M-CF 3 COO]': 509.
In S Example 57 1-[3-(4-Cyanophenoxy)propyl]-3(R) (2-hydroxy-2,2-dithien-2-ylacetoxy)- 1-azoniabicyclo [2.2.2]octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 180 mg 53%. 1 H- NMR (DMSO-d6): 5 1.65 2.2 6H), 2.3 1H), 3.2 1H), 3.3 3.55 6H), 3.95 1H), 4.15 2H), 5.25 1H), 7.0 2H), 7.1 2H), 7.15 2H), 2H), 7.8 2H); MS 509; mp 158 0
C.
Example 58 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxyphenoxy) propyl]-1-azonia bicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 19 mg 18%. NMR (DMSO-d6): 5 1.65 2.15 6H), 2.15 1H), 3.2 1H), 3.3 3.5 6H), 3.75 3H), 3.95 1H), 4.0 2H), 5.25 1H), 6.55 3H), 7.0 2H), 7.2 3H), 7.55 3H); MS [M-CF3COO]*: 514.
Example 59 3 (R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-I-[3-(4-methoxyphenoxy) propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 14 mg 13%. NMR (DMSO-d6): 5 1.65 2.15 6H), 2.35 1H), 3.2 1H), 3.3 3.55 6H), 3.7 3H), 3.9 -4.0 3H), 5.25 1H), 6.9 4H), 7.0 2H), 7.15 2H), 7.5 3H); MS [M-CF3COO]': 514.
44 Example 1-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2 00 -ylacetoxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 19 mg 17%. NMR (DMSO-d6): 1.65 2.15 7H), 2.3 1H), 3.15 1H), 3.25 3.5 Cm, 6H), 3.9 4.0 (m, C 3H), 5.25 1H), 5.95 2H), 6.4 1H), 6.65 1H), 6.85 (d, C 1 7.0 2H), 7.2 2H), 7.5 3H); MS (M-CF 3 COO]': 528.
CI Example 61 l-[3-(2-Carbamoylphenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2ylacetoxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 18 mg NMR (DMSO-d6): 5 1.65 2.0 (mn, 4H), 2.2 2H), 2.3 1H), 3.15 1H), 3.25 3.55 6H), 3.95 1H), 4.15 2H), 5.25 1H), 7.0 7.2 6H), 7.4 7.6 (m, 6H), 7.7 1H); MS [M-CFCOO]*: 527.
Example 62 1-[3-(3-Dimethylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-y lacetoxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 19 mg 17%. NMR (DMSO-d6): 5 .1.65 2.15 6H), 2.3 1H), 2.85 6H), 3.1 3.5 3.85 4.0 (m, 3H), 5.25 1H), 6.2 1H), 6.25 1H), 6.35 1H), 7.0 Cm, 2H), 7.1 1H), 7.2 2H), 7.5 3H); MS [M-CF3COO]': 527.
Example 63 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-nitrophenoxy)propyl ]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 22 mg 20%. NMR (DMSO-d6): 5 1.65 Cm, 4H), 2.2 2H), 2.3 1H), 3.2 1H), 3.3 3.5 6H), 3.95 1H), 4.2 2H), 5.25 1H), 7.0 2H), 7.15 4H), 7.5 3H), 8.15 2H); MS [M-CF 3 COO]': 529.
Example 64 3(R) (2-Hydroxy-2,2-dithien-2-ylacetoxy)-1- [3-(3-nitrophenoxy) 00 propyl]-1-azoniabicyclo [2.2.2)octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 18 mg 16%. H- NMR (DMSO-d6): 6 1.65 2.2 6H), 2.3 1H), 3.15 3.55 7H), 3.95 1H), 4.2 (t, 2H), 5.25 1H), 7.0 2H), 7.2 2H), 7.45 (dd, 1H), 7.55 (m, Cr 3H), 7.6 1H), 7.75 1H), 7.85 1H); MS [M-CF 3 COO]*: 529.
CI Example 1-[3-(4-Acetylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2ylacetoxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 19 mg 17%. NMR (DMSO-d6): 5 1.65 2.15 6H), 2.0 3H), 2.3 1H), 3.2 1H), 3.3 3.55 6H), 3.9 4.0 3H), 5.25 1H), 6.85 2H), 7.0 2H), 7.2 (m, 2H), 7.5 SH), 9.8 1H); MS [M-CFCOO]P: 541.
Example 66 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxycarbonylphen oxy)propyl]-1-azoniabicyclol2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c ahd b. The yield of final step was 18 mg 16%. NMR (DMSO-d6): 5 1.65 2.2 6H), 2.3 1H), 3.2 1H), 3.3 3.5 6H), 3.85 3H), 3.95 1H), 4.1 2H), 5.25 1H), 7.0 2H), 7.15 2H), 7.25 (dd, 1H), 7.45 7.6 6H); MS [M-CF 3 COO]*: 542.
Example 67 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-l-{3-[4-(3-hydroxypropyl) phenoxylpropyl}-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 14 mg 13%. NMR (DMSO-d6): 5 1.6 2.15 8H), 2.3 1H), 2.55 2H), 3.2 1H), 3.25 3.55 (m, 9H), 3.85 4.0 3H), 4.45 OH), 5.25 1H), 7.85 2H), (mn, 2H), 7.1 2H), 7.15 2H), 7.5 2H); MS [M-CF3,COO]*: 542.
46 Example 68 00 3(R) (2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxymethylphenoxy) propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 16 mg 15%. NMR (DMSO-d6): 5 1.7 2.2 (m, Cr 6H), 2.35 1H), 3.1 3.5 7H), 3.9 4.05 Cm, 3H), .4.5 (m, Cr 2H), 5.0 OH), 5.15 1H), 6.9 7.05 4H), 7.2 2H), 7.4 1H), 7.5 3H); MS [M-CF 3 COO]*: 514.
Example 69 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxymethylphenoxy) propyl]-l-azoniabicyclo[2.2.2]2octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 16 mg 15%. NMR (DMSO-d6): 5 1.7 2.2 (m, 6H), 2.35 1H), 3.15 3.5 7H), 3.9 1H), 4.05 2H), 4.45 2H), 5, 25 2H), 6.8 1H), 6.9 2H), 7.2 2H), 7.25 1H), 7.5 3H); MS [M-CF 3 COO*: 514.
Example 3(R) (2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxymethylphenoxy) propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 17 mg 16%. NMR (DMSO-d6): 5 1.65 2.2 6H), 2.3 1H), 3.15 3.55 7H), 3.9 4.05 3H), 4.4 2H), 5.1 OH), 5.25 1H), 6.9 2H), 7.0 2H), 7.2 2H), 7.25 2H), 7.5 3H); MS [M-CF 3 COO]': 514.
Example 71 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy) propyl]-l-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 24 mg 19%. NMR (DMSO-d6): 5 1.65 2.15 6H), 2.35 1H), 3.2 1H), 3.25 3.55 6H), 3.95 (m, 1H), 4.0 2H), 5.25 1H), 6.7 -6.85 3H), 6.95 1H), 47 2H), 7.2 2H), 7.5 3H), 8.85 OH); MS [M-CF 3
COO]:
500.
00 Example 72 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxyphenoxy) propyl] -1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The S yield of final step was 16 mg 15%. NMR (DMSO-d6): 5 1.65 -2.1 (m, 6H), 2.3 1H), 3.2 1H), 3.25 3.5 6H), 3.95 3H), C 5.25 1H), 6.7 2H), 6.75 2H), 7.0 2H), 7.2 2H), 3H), 9.0 OH); MS [M-CF 3 COO]*: 500.
Example 73 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxyphenoxy) propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised-according to methods c and b. The yield of final step was 16 mg 15%. NMR (DMSO-d6): 5 1.65 2.15 6H), 2.3 1H), 3.2 1H), 3.3 -3.55 6H), 3.9 4.0 (m, 3H), 5.25 1H), 6.9 -6.0 3H), 7.0 7.1 3H), 7.2 (m, 2H), 7.5 3H), 9.45 OH); MS [M-CF 3 COO]': 500.
Example 74 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-a zoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 21 mg 22%. 1 H- NMR (DMSO-d6): 5 1.65-1.8 (m, 2H), 1.8-2.0 2H), 2.0 2.15 2H), 2.3 1H), 3.05-3.2 (m, 3H), 3.2-3.5 4H), 3.8-3.95 3H), 5.2 1H), 6.05 2H), 6.75 2H), 7.0 2H), 7.15 2H), 7.55 3H);MS [M- CF'COO]*: 457.
Example 3(R) (2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-oxo-4-thien-2- ylbutyl) -1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 18 mg 17%. NMR (DMSO-d6): 5 1.7-1.85 (m, 2H), 1.9-2.1 4H), 2.3 1H), 3.1 2H), 3.15-3.55 7H), 00 3.95 1H), 5.25 1H), 7.0 2H), 7.4 2H), 7.25 1H), 7.55 3H), 7.95 1H), 8.05 1H); MS [M-CF 3 COO]+: 502.
Example 76 CI 3 (R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(1-methyl-[1H]imidazol-2-ylsulfanyl)propyl] -l-azoniabicyclo[2.2.2]octane; S trifluoroacetate eC The title compound was synthesised according to methods c and b. The yield of final step was 26 mg 25%. IH- NMR (DMSO-d6): 5 1.7 2H), 1.85 2.05 4H), 2.3 1H), 3.25 3.5 7H), 3.6 3H), 3.9 1H), 4.2 2H), 5.2 1H), 7.0 3H), 7.15 2H), 7.3 7.5 3H); MS [M-CF 3 COO]+: 504.
Example 77 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azo niabicyclo[2.2.2]octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 430 mg 54%. NMR (DMSO-d6) 1,6-1.8 (m, 2H), 2,3 1H), 3,15-3,3 3.35-3.55(m, 5H), 3,95 1H), 5,25 1H), 7,0 4H), 7,15 2H), 7.4-7,5 4H); MS [M-Br] 460; mp 206 0
C.
Example 78 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-az oniabicyclo[2.2.2]octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 600 mg 77%. NMR (DMSO-d6) 1.6 -1.8 (m, 2H), 1.85 2.1 4H), 2.3 1H), 2.8 2H), 3.1 3.5 (m, 7H), 3.9 1H), 5.2 1H), 6.9 7.05 4H), 7.15 2H), 7.4 1H) 7.5 3H); MS [M-Br] 474; mp 138°C.
Example 79 1-[3-(Benzothiazol-2-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2- ~'~ylacetoxy) -l-azoniabicyclo[2 octane; trifluoroacetate S The title compound was synthesised according to methods c and b. The 00 yield of f inal step was 23i-ng 21%. NMR (DMSO-d6) 1. 65 2 .1 (mn, 6H), 2.3 (mn, 1H), 3.15 (mn, 1H), 3.25 3.5 (in, 6K), 3.85 (mn, 1K), 4.0 Ct, 2H), 5.2 (mn, 1H), 7.0 2H), 7.15 7.25 (m, 1H), 7. 45 (mn, 5H) 7 .7 1H) MS M-C F 3 COO] 5 41.
CI Example 1-(3-Benzyloxypropyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1azoniabicyclo[2.2.2] octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 16 mg 15%. NMR (DMSO-d6) 5 1. 65 (mn, 2H), 1.9 4H), 2.3 (mn, 1H), 3.1 3.4 Cm, 3.5 Ct, 2H), 3.9 (m, 1H), 3.9 Cs, 2H), 5.2 (mn, 1H), 7.0 Cm, 2H), 7.15 Cm, 2H), 7.35 (in, 5H), 7.5 (in, 3H) MS [M-CF 3 COO]': 498.
Example 81 3(R) -(2-Hydroxy-2,2-dithien-2-ylacetoxy) (4-phenylbutoxy) hexyl) -1-azoniabicyclo. [2 octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 560 mg 60%. NMR (CDCl,) 5 1.2 -1.75 (in, 16H), 1.8 -2.1 (mn, 4K), 2.4 Cm, 1K), 2.6 Ct, 2H), 3.3 3.75 (in, 11H), 4.2 Cm, 1H), 5.3 (mn, 1K), 6.0 (bs, OH), 6..95 Cm, 2KH), 7.159 7.3 (in, 9H) MS tM-Br]': 582.
Example 82 3 -(2-Hydroxy-2 ,2-dithien-2-ylacetoxy) -1-(4-phenoxybutyl) -1azoniabicyclo octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 240 ing 30%. NMR (DMSO-d6/0D01 3 5 1.8 1.95 (mn, 6K), 2.1 Cm, 2H), 2.45 (mn, 1K), 3.18 (mn, 1K), 3.5 3.8 (in, 6K), 4.0 Ct, 2K), 4.15 (mn, 1K), 5.15 (mn, 1H), 6.7 Cs, OK), 6.9 5K), 7.15 Cd, 1H), 7.25 Cm, 5K) MS [M-Brl*: 498; mp 161'C.
Example 83 S 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-l- S azoniabicyclo octane; bromide 00 The title compound was synthesised according to methods c and a. The yield of final step was 380 mg 50%. NMR (DMSO-d6) 1.85 (m, 2K), 2.05 2H), 2.4 (in, 1K), 3.6 4.1 7H), 4.35 3H), 5.25 (mn, 1H), 6.0 (bs, OH), 6.9 4H), 7.0 1H), 7.1 (dd, 2H), 7. 2 (dd, 2H) 7. 3 2H); MS [M-Br~ 4 7 0; mp 4 8'C.
Example 84 CI 1-(2-Benzyloxyethyl)-3(R)- (2-hydroxy-2,2-dithien-2-ylacetoxy) -1azoniabicyclo 2.2) octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 17 mg NMR (DMSO-d6) 1.65 (mn, 4H), 2.3 *Cm, 1H), 3.2 3.55 Cm, 7K), 3.85 Cm, 2H), 4.5 Cs, 2H), 5.25 Cm, 1H), 7.0 Ct, 2K), 7.15 Ct, 2K), 7.3 -7.4 Cm, 4H), Cm, 3K) MS [M-CF 3 COO]': 484.
Example 3(S) -(2-Hydroxy-2,2-dithien-2-ylacetoxy) -1-(3-phenoxypropyl) -1azoniabicycJlo[2.2.2] octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 600 mng 54%. NMR CDMSO-d6/CDCl 3 1.85 2.3 Cm, 6K), 2.5 (in, 1H), 3.3 1K), 3.4 1K), 3.5 -3.7 Cm, 4.05 2K), 4.2 Cm, 1H), 5.25 Cm, 1K), 6.85 Cd, 2K), Cm, 3K), 7.15 Cm, 2K), 7.2 Cd, 7.-3 Cm, 4KH); MS (M-Br: 4 84; mp 230'C.
Example 86 4- (2-Hydroxy-2 ,2-dithien-2-ylacetoxy) -1-(3-phenoxypropyl) -1-azonia bicycJlo[2.2.2]octane; bromide The title compound was synthesised according to methods f and a. The yield of final step was 290 mng, 60%. NMR CDMSO-d6) 2. 15 Cm, 2K) 2.35 (mn, 6H), 3.35 2H), 3.65 Cm, 6H), 4.05 Ct, 2K), 6.9 7.05 Cm, 7.1 Cm, 2K), 7.3 Cm, 3H), 7.55 Cm, 2K); MS [M-Br]*:484; mp 1680C.
Example 87 4- (2-Hydroxy-2,2-dithien-2-yl-acetoxy) -l-phenethyl-1-azoniabicyclo [2 00 .2.2]octane; bromide The title compound was synthesised a'ccording to methods f and a. The yield of final step was 260 mg, 57%. 1 H- NMR (DMSO-d6) 62. 35 Cm, 6H) 3. 0 (in, 2H-) 3.4 2H), 3.75 (in, 6H),7. 0 (in, 2H), 7.3 7. 5 6H) C1 7.5 SSCm, 2H) MS [M-Br] 4S4; mp 195'C.
Example 88 ci 1-(3-phenoxypropyl)-3(R)-(2,2--dithien-2-ylpropionyloxy)-lazoniabicyclo 2.2) octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 390 mng NMR (DMSO-d6): 5 1.65-2.20 (in, 6H), 2.10 Cs, 3K), 2.30 Cbs, 1H), 3.10 Cm, 1H), 3.30-3.60 Cm, 6K), 3.95-4.10 Cm, 3H), 5.20 Cm, 1H), 6.90-7.05 Cm, 5H), 7.05-7.10 Cm, 2H), 7.25-7.35 (in, 2H) 7.50 Cm, 2H); MS 482; mp 170'C.
Example 89 3(R) -(2-Hydroxy-2 ,2-dithien-3-ylacetoxy) -1-(3-phenoxypropyl) -1azoniabicyclo octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 300 mg, 7 NMR (DMSO-d6) 1. 6 Cm, 1K) 1.75 Cm, 1K), 1.8 -2.0 Cm, 2KH), 2.0 2.2 (in, 2K), 2.3 Cm, 1K), 3.15 Cm, 1K), 3.3 -3.6 (mn, 6H), 3.9 (in, 1H), 4.05 Ct, 2K), 5.2 (in, 1K), 6.75 OK), 6.95 Cm, 3H), 7.15 (in, 2K), 7.3 2K), 7.4 7.5 (in, 4H); MS 484; mp 21900.
Example 3 -(2-Hydroxy-2 ,2-dithienyl-3-ylacetoxy) -1-(3-thien-2-ylpropyl) -1azoniabicyclo octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 300 ing, 77%. NMR (DMSO-dE) 1.5-1.6 (m, 1K), 1.6-1.75 1H), 1.8-2.1 4K), 2.25 1K), 2.8 t, 2K), 3.05-3.5 Cm, 7K), 3.8-3.95 (in, 1K), 5,15 Cm, 1H), 6.75 Cs, OH), 6.9-7.0 (mn, 2K), 7. 1 Cm, 2K) 7.35-7. 55 5K) MS [M-BrP': 474 mp S52 192°C.
00 Example 91 3(R)-(2-Hydroxy-2,2-dithien-3-yl-acetoxy)-1-phenethyl-l-azoniabicyclo [2.2.2]octane; trifluoroacetate S The title compound was synthesised according to methods c and b. The Cr yield of final step was 63 mg, 48%. IH- NMR (DMSO-d6): 6 1.5-1.7 (m, Cr 1H), 1.7-1.85 1H), 1.9-2.1 2H), 2.3 1H), 2.9-3.1 2H), S 3.15-3.6 7H), 3.9-4.0 1H), 5.2 1H), 6.8 OH), 7.1 (m, (C 2H), 7.25-7,35 5H), 7.4 2H), 7.5 2H); MS [M-CF3COO]*: 454.
Example 92 (2-Hydroxy-2,2-dithien-3-yl-acetoxy) (3-phenylpropyl)-1-azonia bicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 75 mg, 55%. 1 H- NMR (DMSO-d6) 5 1.5-2.0 (m, 6H), 2.25 1H), 2.5-2.6 2H), 3.05-3.6 8H), 3.8-3.9 (m, 1H), 5.15(m, 1H), 6.75 OH), 7.1 2H), 7.2-7,35 5H), 7.4 2H), 7.5 2H); MS [M-CF3COO] 468.
Example 93 3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy) -1-(4-phenylbutyl)-1-azoniab icyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 68 mg, 48%. NMR (DMSO-d6): 6 1.5-1.8 (m, 6H), 1.8-2.0 2H), 2.25 1H), 2.6 2H), 3.05 1H), 3.15-3.45 6H), 3.85 1H), 5.15(m, 1H), 6.75 OH), 7.1 (d, 2H), 7.2 2H), 7,3 3H), 7.4 2H), 7.5 2H) MS [M- CF3COO]': 482.
Example 94 3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azo niabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 65 mg, 49%. IH- NMR (DMSO-d6) 5 1.5-1.65 (m, 53 1H), 1.65-1.78 1H), 1.85-2.05 (mn, 2H), 2.3 1H), 3.1-3.6 (m, 9H), 3.95 (mn, 1H), 5,2 1H), 6.75 OH), 7.0 2H), 7.15 (m, 00 2H), 7.45 3H), 7,5 2H); MS [M-CF3COO]*: 460.
Example 3(R) (2-Hydroxy-2,2-dithien-3-ylacetoxy) (4-phenoxybutyl) -1-azonia CI bicyclo[2.2.2] octane; trifluoroacetate C The title compound was synthesised according.to methods c and b. The yield of final step was 63 mg, 43%. NMR (DMSO-d6): 5 1.5-2.0 (m, C 8H), 2.3 1H), 3.1 1H), 3.2-3.5 6H), 3.85 1H), 2H), 5.2(m, 1H), 6.75 OH), 6.95 3H), 7.1 2H), 7.2 (m, 2H), 7,3 2H), 7.45 2H), 7.5 2H); MS [M-CF3COO]*: 498.
Example 96 3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-phenoxyethyl)-1-azonia bicyclo[2.2.2octane; trifluoroacetate The title compound was synthesised according to methods c and b..The yield of final step was 72 mg, 52%. NMR (DMSO-d6): 5 1.55-1.65 (m, 1H), 1.7-1.8 1H), 1.85-2.05 2.3 1H), 3.2-3.6 (m, 5H), 3.7 4.05 1H), 4.4 2H), 5.2(m, 1H), 6.75 (s, OH), 6.95-7.05 3H), 7.1 2H), 7.3-7.5 6H); MS [M-CF3COO]*: 470.
Example 97 1-[3-(4-Fluorophenoxy)propyl-3(R)-(2-hydroxy-2,2-dithien-3-ylacetox y)-l-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 79 mg, 54%. NMR (DMSO-d6): 5 1.55-1.65 (m, 1H), 1.7-1.8 1H), 1.85-2.0 2H),2.05-2.2 2H), 2.3 (m, 1H), 3.1-3.2 1H), 3.25-3.55 6H), 3.85-3.95 1H), 4.0 (t, 2H), 5.2(m, 1H), 6.75 OH), 6.95 2H), 7.15 4H), 7.4 (m, 2H), 7.5 2H); MS [M-CF3COO]-: 502.
Example 98 3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenylallyl)-1-azoniab icyclo .2)octane; trifluoroacetate S The title compound was synthesised according to methods c and b. The 00 yield of final step was 124 mg. 17%. NMR (DMSO-d6)~ 1.8 -2.05 (mn, 4H), 2.3 1H), 3.15 (mn, 1H), 3.3 3.5 (mn, 4H), 3.9 (mn, 1H), 4.05 (in 2H), 5.25 (in, 1K), 6.35 (mn, 1H), 6.75 OH), 6.85 1H), 1 (mn, 2H) 7 5 (mn, 5K) 7. 55 (in, 4H-) MS [M-CF3C00I': 502.
Example 99 1-(3-phenylallyl)-3(R)-C9-Hydroxy-9[H-fluorele-9-carbolyloxy)-lazoniabicyclo [2 octane; bromide The title compound was synthesised according to methods c and a. The yield of' f inal step was 400 mg NMR (DMSO-d6) 1. 35-1. 50 (mn, 1K), 1.60-1.75 (mn, 1K), 1.75-1.95 (mn, 2H), 2.10 (in, 1H), 2.85 (mn, 1H), 3.10 1K), 3.20-3.50 (in, 3K), 3.85 (in 1H), 4.0 (dd, 2K), 5.05 (mn, 1H), 6.40 (dd, 1K), 6.80-6.90 1K), 6.85 OK), 7.20-7.50 (mn, 7K), 7. 60 (mn, 4H) 7. 80 (mn, 2H) MS [M-Br] 452; mp 14 6'C.
Example 100 3 -(9-Hydroxy-9 -fluorene-9-carbonyloxy) -1-(3-phenoxy-propyl) 1-azoniabicyclo[2 octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 690 mng 83%. NMR (DMSO-d6) :5 1.4-7 (in, 1K), 1.68 (mn, 1K), 1.87 (in, 2H), 2.1 (in, 3H), 2.89 (mn, 1K), 3.15 (d, 1H), 3.4 (mn, 5K), 3.9 (mn, 1K), 4.0 (mn, 2K), 5.04 (in, 1K), 6.85 OK), 6.97 (mn, 3K), 7.35 (mn, 4K), 7.45 (mn, 2K), 7.65 (in, 7.85 (mn, 2H); MS 470; mp 10800.
Example 101.
3(R)-C9-Hydroxy-9[H]-fluorene-9-carbofyloxy)lphenethyl-l azoniabicyclo [2.2 octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 170 mng, 74%. NMR (DMSO-d6) 1.45 (mn, 1H) 1.65 (mn, 1K), 1.85 (mn, 2K), 2.1 (mn, 1K), 2.9 (mn, 3K), 3.15 (mn, 1K), 3.3 3.5 (mn, 5K), 3.85 (in, 1H), 5.05 (mn, 1K), 6.85 OK), 7.2 7.4 (mn, 7H), 7.45 2H), 7.55 1K), 7.65 1KH), 85 (d, 2h-) MS [M-BrP': 440; mp 1180C.
00 Example 102 3(R) -(9-Hydroxy-9 -fluorene-9-carbonyloxy) -1-(2-phenoxyethyl) -1azoniabicyclo octane; bromide *The title compound was synthesised according to methods c and a. The yield of final step was 460 ing, 96%. NM?. (DMSO-d6) 1.42 1H), 1.66 (in, 1H), 1.80-1.88 (mn, 2H), 2.08 1H), 2.93 3.25 -3..60 (mn, 4H), 3.65 (mn, 3.95 (in, 4.35 (m 2H), 5.02 (mn, 1H), 6.85 C1 1H, OH), 6.97 2H), 7.04 Ct, 1H), 7.20-7.45 Cm, 6H), 7.55-7.60 2H) 7.80 2H) MS 456; rnp 14000.
Example 103 3(R) -(9-Hydroxy-9 (H)-fluorene-9-carboiyloxy) -1-(4-oxo-4-phenylbuty1) -1-azoniabicyclo[2 .2.2)octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 15 mg, 15%. NM?. (DMSO-d6): 1.45 (in, 1H), 1.65 1H), 1.7 -2.0 (mn, 4H), 2.1 (mn, 1H), 2.75 (in, 1H), 3.0 3.2 (m 4H), 3.25 -3.4 4H), 3.85 (in, 1H), 5.05 (mn, 1H), 6.85 OH), 7.35 Ct, 2H), 7.45 2H), 7.55 -7.7 (in, 5H), 7.85 (d, 2H), 8.0 2H); MS [M-CF3COO]': 482 Example 104 1- (4-Fluorophenoxy)propyl) -(9-hydroxy-9 -fluorene-9carbonyloxy) -1-azoniabicyclo(2 .2.2]octane; chloride The title compound was synthesised according to methods c and a. The yield of final step was 440 ing, 94%. NM?. CDMSO-d6) 1.4 (mn, 1H) 1.65 (in, 2H), 1.7 -1.95 2H), 2.0 2.1 (mn, 3H), 2.8 1H), 3.1 1H), 3.2 -3.4 3.8 1H), 4.0 Ct, 2H), 5.0 (mn, 6.85 OH), 6.95 (in, 2H), 7.15 7.35 2H), 7.45 2H), 7.55 1H), .7.65 1H), 7.85 Cd, 2H); MS 488; mp 14200.
Example 105 -[3-(2,4-Difluorophenoxy)propyl)-3(R)-(9--hydroxy-9[H]-fluorene-9- 56 Scarbonyloxy) -1-azoniabicyclo octane; trifluoroacetate S The title compound was synthesised according to methods c and b. The 00 yield of final step was 14 mg, 13%. NMR .(DMSO-d6) '5 1.4 1H) 1.6 1.9 (mn, 3H),'2.1 3H), 2.8 (in, 3.1 1H), 3.2 3.4 (mn, 5K), 3.85 1H), 4.05 2H), 5.0 (in, 1H), 6.85 OH), 7.05 1H), 7.15 7.4 (in, 4H), 7.45 2H), 7.55 1H), 7.65 1K), 7.85 2H) MS [M-CF 3 COOI': 506.
Example 106 3- 3(R) (9-Hydroxy-9[H) -fluorene-9-carbony.oxy) (3-phenylaminopropyl) -1-azoniabicyclo [2.2 .2)octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 14 mg, 15%. NMR (DMSO-d6) 5 1.4 1H) 1.6 1H), 1.8 (mn, 4H), 2.05 Cm, 1H), 2.7 Cm, 1F), 3, 0 (mn, 3H), 3.2 3.4 Cm, 6H), 3.8 Cm, 1K), 5.0 Cm, 1K), 5.6 Ct, NH), 6.55 Cm, 3H), 6.85 OK), 7.1 Ct, 2H), 7.35 (dd, 2K), 7.45 Cdd, 2H), 7.55 Cdd, 2K), 7.8 2K); MS [M-CF 3 COO]': 469.
Example 107 3(R) -(9-Hydroxy-9[H] -fluorene-9-carbonyloxy) (4-hydroxyphenoxy) propyl) -1-azoniabicyclo[2 .2 .2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 15 mg, 15%. NMR (DMSO-d6) '5 1.4 Cm, 1H) 1.6 Cm, 1K), 1.7 1.9 Cm, 2H), 1.95 2.05 Cm, 2K), 2.1 Cm, 1K), 2.8 Cm, 1H), 3.1 Cd, 1K), 3.25 3.4 Cm, 5K), 3.8 3.9 Cm, 3H), Cm, 1H), 6.7 Cd, 2H), 6.75 Cd, 2H), 6.85 Cs, OH), 7.35 2H), 7.45 Ct, 2K), 7.55 Cd, 1H), 7.65 Cd, 1K), 7.85 Cd, 2H), 9.0 Cs, OH); MS [M-CF 3 000P': 486.
Example 108 1- (2-Benzyloxyethyl) -(9-hydroxy-9 -fluorene-9-carbonyloxy) -1azoniabicyclo octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 470 mg, 96%. IK- NMR (DMSO-d6) 5 1 .4 1K) 1.65 Cm, 1K) 1.7 1.9 Cm, 2K) 2.1 Cm, 1K) 2.9 Cm, 1K) 3.15- 57 3. 5 (in, 6H), 3.75 (mn, 2H), 3.85 (in, 1H), 4 .5 2H), 5. 0 (mn, 1H), S 6.85 OH), 7. 3 7. 5 9H), 7.55 (mn, 2H), 7. 8 2H); 00 MS 470; mp 8 6 0
C.
Example 109 3(R) -(9-Hydroxy-9H-fluorene-9-carbonyloxy) -1-(3-thienyl-2-ylpropyl) 1-azoniabicyclo[2 .2.2]octane; bromide The title compound was synthesised according to methods c and a. The yield of final- step was 180 ing, 70%. NMR (DMSO-d6) 6 1.37 (in, 1i 1.62 (in, 1H), 1.75-1.95 (mn, 4H), 2.06 (mn, 1H), 2.72 (mn, 1H), 2.80 (in, 2H), 3.02-3.06 (in, lH), 3.15-3.20 (in, 2H), 3.25-3.40 (in, 3H), 3.80 (in, 1H), 5.0 (in, 1H), 6.85 lH, OH), 6.95-7.0 (in, 2H), 7.25-7.50 (in, 7 .55 65 (in, 2 H) 7. 85 2H) MS [tM-Brl 4.60; mp 140 0
C.
Example 110 3 -(9-Hydroxy-9H-fluorene-9-carbonyloxy) -1-(3-phenyipropyl) -1-azon iabicyclo [2 octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final s tep was 80 mg, 40%. NMR (DMSO-d6) 5' 1. 35 (in, 1H) 1.6 (in, 1H), 1.7-1.90 (in, 2H), 2.05 (in, 1H), 2.5 (in, 2H), 2.7 (in, 1H), (in, 1H), 3.15 2H), 3.2-3.4 (mn, 3H), 3.75 1H), 5.0 (in, 1H), 6.85 OH), 7.20-7.50 (in, 9H), 7.55 (dd, 2H), 7.85 2H); MS [M- CF3COO]': 454.
Example 111 3 -(9-Hydroxy-9H-fluorene-9-carbonyloxy) -1-(4-phenylbutyl) -1-azoni abicyclo octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 74 mg, 35%. NMR (DMSO-d6): 5 1. 35 1H) 1.45-1.65 (in, 5H), 1.7-1.90 (mn, 2H), 2.05 (in, 1H), 2.55-2.75 (mn, 3K), (in, 1H), 3.15 -3.45 (mn, SH), 3.75 1K), '5.0 1H), 6.85 Cs, OH), 7.20 (in, 3H), 7.25 7.35 (in, 4H), 7.45-7.5 (in, 2H), 7.55-7.6 (dd, 2H) 7.85 (di, 2K); MS [M-CF3COOJ': 468.
Example 112 3 (9-Hydroxy-9H-fluorene-9-carboflyloxy-l- (2-thienyl-2-ylethyl) -1- S azoniabicyclo [2.2 .2)octane; trifluoroacetate 00 The title compound was synthesised according to methods c and b. The yield of final step was 7 9 mg, 39%. NMR (DMSO-d6) 1. 4 (in, 1H1), 1.65 (mn, IH), 1.8-1.95 (in, 2H), 2.1 (mn, lH), 2.9 (mn, 1H), 3.1-3.25 (mn, 4H), 3.15 -3.45 (mn, 5H), 3.85 (mn, 1H), 5.05 (mn, iH), 6.85 (s, OH), 7.0 2H), 7.35 2H), 7.45-7.5 3H), 7.55 1H), 7.65 1H) 7. 85 2 H) MS [M-C F3COO]'46.
CIExample 113 3(R) -(9-Hydroxy-9H-fluorene-9-carbolyloxy) -1-(4-phenoxybutyl) -1-azon iabicyclo [2.2 .2 Joctane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 72 mg, 33%. NMR (DMSO-d6) 1. 4 1H), 1.55-1.9 (in, 7H), 2.05 (mn, 1H), 2.7 Cm, 3.0 (in, 1H), 3.15 (in, 7H), 3.8 Cm, 1H), 4.0 (in, 2H), 5.05 (in, 1H), 6.85 OH), 6.95 (in, 3H), 7.25-7.35 Cm, 4H), 7.4-7.45 2H), 7.6 (dd, 2H), 7.85 (d, 2H); MS [M-CF3000] 484.
Example 114 3(R) -(9-Methyl-9 -fluorene-9-carbonyloxy) -1-(3-phenylallyl) -1azoniabicyclo[2 octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 200 mng NMR CDMSO-d6) :5 1.54 Cm, 1H) 1.70-1.86 (in, 1.76 Cs, 3H), 2.13 (mn, 1H), 3.06 Cm, 1N) 3.20-3.50 Cm, 4H), 3.86 Cm, 1H), 4.05 Cdd, 2H), 5.02 1H), 6.43 (dd, 1H), 6.86 Cd, 1H) 7.26-7..46 Cm, 7H), 7.58-7.65 3H) 7.70-7.72 Cm, 1H) 7.87-7. 90 Cm, 2H) MS 450; mp 234'C.
Example 115 3 CR) -(9-Methyl-9 -fluorene-9-carbonyloxy) -1-(2-phenoxyethyl) -1-azo niabicyclo [2 2] octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 210 ing NMR (DMSO-d6) 1 .55 Cm, 1H), 59 1 .60-2.0 (1n 3M) 176 3H) 2.12 (mn, 1H) 3.10-3.25 1H), S 3.40-3.80 6M), 4.0 (mn, 4.41 2H), 4.98 (mn, 1H), 6.98-7.05 00 (mn, 3M), 7.27-7.46 (mn, 6H) 7.63-7.71l (mn, 2H) 7.87-7.90 (mn, 2H) MS 454; np 202 0
C.
Example 116 (9-MethyJ-9[H]-fluorene -9-carboflyloxy).1I-(3-phefloxypropyl)-lazon iabicyclo[2.2.2] octane; bromide The title compound was synthesised according to methods c and a.-The yield of final step was 210 mng NMR (DMSO-d6) :5 1.55 (in,1H), 1.60-2.0 (mn, 3M), 1.78 3H), 2.0-2.20 (mn, 3M), 3.0-3.10 (in,1H), 3.25-3.53 (mn, 6H), 3.86 1H), 4.03 (mn, 2H), 4.98 (mn, 1H), 6.95- (mn, 3H), 7.30-7.48 (in, 6H), 7.65--7.92 mn, 4H); MS 468; np, 204 0 C Example 117 3(R)-(9-Methyl-9[H]-fluorene-9-carbolyloxy)-1-pheethyl-lazoniabicyclo [2.2 ]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 18 mg, 19%. IH- NMR (DMSO-d6) 5 1. 55 (mn, 1M) 1.65 1.95 (in, 3M), 1.75 3M), 2.15 (in, 1M), 2.9 3.1 (mn, 4H), 3.25 3.55 (mn, 5M), 3.85 1M), 5.05 (mn, 1H), 7.25 7.55 (mn, 9H), 7.65 1H), 7.75 lM), 7.95 2M) MS [M-CF 3 000J': 438.
Example 118 3(R) -(9-Methyl-9 -fluorene-9-carbonyloxy) -1-(4-oxo-4-phenylbutyl) 1-azoniabicyclo [2.2 octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 19%. NMR (DMSO-d6) :5 1.55 (mn, lM) 1. 65 2.O05 (mn, SM), 1. 21(i, iM) 3.0 1M), 3.1 (mn, 8M), 3.85 (mn, 1M), 7.35 7.5 (in, 4H), 7.55 2M), 65 (t, 2H), 7.7 1M), 7. 9 2MH), 8. 0 2H) MS [M-CF 3 COO]': 480.
Example 119 3 5 1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl9Hfluorene-9 carbonyloxy)-1-azoniabicyclo[:2.2.2)octane; trifluoroacetate The title compound was synthesised according to methods c and b. The 00 yield of final step was 23 mg, 23%. NMR (DMSO-d6): 6 1.55 1H), 1.65 1.95 3H), 1.75 3H), 2.05 2.15 3H), 3.0 (mn, 1H), 3.25 3.5 6H), 3.85 1H), 4.0 2H), 5.0 1H), 6.95 Cm, 2H), 7.15 2H), 7.35 7.5 4H), 7.65 1H), 7.75 (d, c 7.9 2H); MS [M-CF 3 COO]': 486.
Example 120 C 1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9H-fluorene-9carbonyloxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 20 mg, 19%. NMR (DMSO-d6): 6 1.55 1H), 1.65 1.95 3H), 1.75 3H), 2.05 2.2 3H), 3.0 1H), 3.25 3.55 6H), 3.85 1H), 4.1 2H), 5.0 1H), 7.05 1H), 7.2 7.5 6H), 7.65 1H), 7.75 1H), 7.9 (d, 2H); MS [M-CF3COO]': 504.
Example 121 3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylaminopropyl)- 1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 19%. NMR (DMSO-d6): 5 1.55 Cm, 1H), 1.65 1.95 5H), 1.75 3H), 2.1 1H), 2.95 1H), 3.05 2H), 3.15 3.45 6H), 3.8 1H), 5.0 1H), 5.65 (t, NH), 6.6 3H), 7.1 2H), 7.35 7.55 4H), 7.65 1H), 7.75 1H), 7.9 2H); MS [M-CFCOO]': 467.
Example 122 1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9-methyl-9[H]-fluorene-9carbonyloxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 22 mg, 22%. NMR (DMSO-dG): 6 1.55 1H), 1.65 1.9 3H), 1.75 3H), 2.0 2.15 3H), 3.0 1H), 3.25 3.5 6H), 3.8 3.95 3H), 5.0 1H), 6.7 1H), 61 S 6.75 1H), 7.35 7.45 4H), 7.65 1H), 7.75 1H), 7.9 2H), 9.0 OH); MS [M-CF 3 COO]: 484.
00 Example 123 1-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-a zoniabicyclo[2.2.2]octane; trifluoroacetate C The title compound was synthesised according to methods c and b. The C yield of final step was 17 mg, 17%. NMR (DMSO-d6): 5 1.55 1H), 1.65-1.95 4H), 1.75 3H), 2.15 1H), 3.1 1H), 3.3- C 3.55 6H), 3.8-3.95 3H), 4.5 2H), 5.0 1H), 7.3-7.5 9H), 7.6-7.7 2H), 7.9 2H); MS (M-CF 3 COO]': 468.
Example 124 3(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-phenethyl-1-azoniabicy clo[2.2.2]octane; bromide The title compound was synthesised according to methods d and a. The yield of final step was 420 mg NMR (DMSO-d6): 5 1.55 1H), 1.65-1.95 3H), 2.15 1H), 2.95 2H), 3.15 1H), 3.25-3.60 6H), 3.85 1H), 3.95-4.15 (dd, 2H, J1= 1.8 Hz, J2= 4.2Hz), 5.02.
1H), 5.25 1H), 7.25-7.43 11H), 7.48-7.55 2H); MS [M- Br]: 438; mp 216 0
C.
Example 125 3(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-az oniabicyclo[2.2.2]octane; bromide The title compound was synthesised according to methods d and a. The yield of final step was 450 mg NMR (DMSO-d6): 5 1.56 1H) 1.65-1.95 Cm, 3H), 2.05-2.15 3H), 3.10 1H), 3.20-3.50 6H), 3.80 1H), 3.94-4.14 4H), 5.0 1H), 5.22 1H), 6.94-7.0 3H), 7.25-7.35 6H), 7.40 2H), 7.54-7.47 2H); MS [M- 468; mp 1570C.
Example 126 1-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-azoniabicyclo [2.2.2]octane; bromide 62 The title compound was s ynthesised according to methods d and a. The yield of final step was 83 mg NMR CDMSO-d6) 5 1.50-2.0 (m, 00 8H), 2.15 (in, 1H), 2.65 2H), 3.05-3.65 7H), 3.80 Cm, 1H), Cm, 119), 5.30 1H), 7.10-7.45 (in, 11H), 7.45-7.60 Cm, 2H); MS [M- BrIP: 468; mp 951C.
CI Example 127 cI 1- (2-Phezxoxyethyl) -(9[H]-xantherxe-9-carbonyloxy) -l-azoriiabicyclo [2.2.2]octane; bromide The title compound was synthesised according to methods d and a. The yield of final step was 300 mng 73%. NMR CDMSO-d6) 1 .70-2. 0 Cm, 4K), 2.2 Cm, 3.20-3.80 Cm, 7H), 4.0 Cm, 1H), 4.40 Cm, 2H), 5.05 (in, 1H), 5.30 Cs, 1H), 7.0-7.10 (in, 7H), 7.30-7.45 Cm, 4H), 7.45-7.55 Cm, 2K); MS 456; mp 20000.
Example 128 1- (3-Phenoxypropy.) -3 (9 -xanthene-9-carbonyloxy) azoniabicycio [2.2.2)octane; bromide The title compound was synthesised according tomethods d and a. The yield of final step was 350 mg 83%. NMR (DMSO-d6).: 5 1.70-2.0 (in, 4K), 2.0-2.25 Cm,3K), 3.15-3.65 Cm, 7H), 3.85-3.95 Cm, 1K), 3.95-4.10 Cm, 2K), 5.0 1H), 5.30 Cs, 1K), 6.90-7.0 Cm, 3H), 7.10-7.25 Cm, 4H), 7.25-7.40 Cm, 4K), 7.40-7.60 Cm, 2K); MS [M-Brl*: 470; mp 18400.
Example 129 1-Phenethyl-3 -xanthene-9-carbonyloxy) -1-azoniabicyclo (2.2.2joctane; bromide The title compound was synthesised according to methods d and a. The yield of final step was 100 ing, 4 NMR CDMSO-d6) 1. 65 0 (in, 4K), 2.1 1H), 2.9 3.05 2K), 3.15 3.6 Cm, 7K), 3.85 1H), 5.05 1K), 5.3 7.15 7.55 13H); MS 440.
Example 130 1-(4-Oxo-4-phenylbutyl)-3(R) -(9[H]-xanthene-9-carbonyloxy)-l-azonia 63 S bicyclo[22.2]octane; trifluoroacetate The title compound was synthesised according to methods d and b. The 00 yield of final step was 16 mg, 15%. NMR (DMSO-d6): 5 1.65 2.05 Cm, 6H), 2.1 1H), 3.1 3.55 9H), 3.8 1H), 5.05 (m, 1H), 5.25 1H), 7.1 7.3 4H), 7.35 2H), 7.45 7.6 (m, 4H), 7.7 1H), 8.0 1H); MS [M-CF 3 COO]): 482.
CI Example 131 1-[3-(4-Fluorophenoxy)propyl] -3(R)-(9[H]-xanthene-9-carbonyloxy)-1- S azoniabicyclo[2.2.2]octane, trifluoroacetate The title compound was synthesised according to methods d and b. The yield of final step was 18 mg, 18%. NMR (DMSO-d6): 5 1.7 2.1 (m, 6H), 2.15 1H), .3.1 3.5 7H), 3.8 1H), 4.0 2H), 1H), 5.3 1H), 6.95 2H), 7.1 7.3 6H), 7.4 (t, 2H), 7.5 (dd, 2H); MS [M-CF 3 COO]': 488.
Example 132 1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy) -1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods d and b. The yield of final step was 14 mg, 14%. NMR (DMSO-d6): 5 1.65 1.95 4H), 2.05 2.2 3H), 3.1 3.55 7H), 3.8 1H), 4.05 2H), 5.0 1H), 5.3 1H), 7.05 1H), 7.1 7.55 (m, MS [M-CF3COO)*: 506.
Example 133 1-(3-Phenylaminopropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods d and b. The yield of final step was 17 mg, 17%. 1 H- NMR (DMSO-d6): 6 1.65 2.0 (m, 6H), 2.15 1H), 3.0 3.5 9H), 1.75 1H), 5.0 1), 5.3 1H), 6.65 NH), 6.55 3H), 7.05 7.3 6H), 7.35 7.55 4H); MS [M-CF 3 COO*: 469.
Example 134 64 1- (4-Hydroxyphenoxy)propyl) -3 (9[(H]-xanthene-9-carbonyloxy) -1azoniabicyclot2 octane; trifluoroacetate 00 The title compound was synthesised according to methods d and b. The yield of fin~al step was 21 mg, YH- NMR (DMSO-d6) :5 1. 7 2. 1 (m, 6H), 2 .15 (mn, 1H), 3.1 3.5 (in, 7H), 3.7 3.95 Cm, 3H), 5.0 (in, 1H), 5.3 1H), 6.7 2H), 6.75 2H), 7.1 7.3 (mn, 4H) 7.35 7.55 4H), 9.0 OH); MS [M-0F 3 000]': 486.
Example 135 Cl l-(2-Benzyloxyethyl)-3(R)-(9[H)-xanthene-9-carbonyloxy)-lazoniabicyclo [2 octane; trifluoroacetate The title compound was synthesised according to methods d and b. The yield of final step was 16 mg, 16%. 1 H- NMR (DMSO-d6) 1.65 1.95 (in, 4H), 2.1 (in, 3.1 3.9 (in, 10H), 4.5 2H), 5.0 Cm, 1H), 5.3 1H), 7.15 (mn, 4H), 7.3 -7.5 Cm, 7H), 7.55 2H); MS [M-CF 3 COOI*: 470.
Example i36 3 (9-Hydroxy-9 -xanthene-9-carbonyloxy) (3-phenoxypropyl) -1azoniabicyclo[2.2.2]octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 340 mg 71%. NMR (DMSO-d6): 6 1.30 (in, 1H) 1. 65 (in, 1H) 1. 70-1. 95 (in, 2K) 1. 95-2. 10 (mn, 3H) 2.70 (in, 1H), 2.90 (in, 1H), 3.2-3.5 (mn, 5H), 3.80 1H), 4.0 Ct, 2H), 5.05 Cm, 1H), 6.90-7.0 (in, 3H), 7.20-7.35 7K), 7.40-7.46 2K), 7.65-7.70 Cm, 2H); MS 486; mp 21900.
Example 137 3(R) -(9-Hydroxy-9 -xanthene-9-carbonyloxy) -1-phenethyl-1-azoniabi cycloE2.2.2]octane; bromide The title compound was synthesised according to methods c and a. The 'yield of final step was 290 mg 64%. NMR (DMSO-d6) 5 1.32 (m, 1H), 1.65 (in, 1K), 1.70-1.95 (in, 2H), 2.1 1K), 2.75-2.90 3H), 3.05 1K), 3.30-3.50 Cm, 5K), 3.82 1K), 5.05 1K), 7.20-7.40 10H), 7.40-7.50 Cm, 2K), 7.65-7.70 Cm, 2H); MS 456; mp 2210C 00 Example 138 3 (9-Hydroxy-9H-xanthene-9-carbonyloxy) (3-thien-2-ylpropyl) -1azoniabicyclo octane; bromide The title compound was synthesised according to methods c and The yield of final step was 310 mg 'H NMR (DMSO-d6) :5 1. 30 .Cm, CI1H) 1. 62 (in, 1H) 1. 70-1. 90 C,4H) 2. 05 (m,1H) 2. 60 1H), 2.75-2.85 (in, 4K), 3.15 Cm, 2H), 3.25-3.40 (in, 3.75 1H), 1H) 6. 93 H) .7.0 1K) 7.14-7.26 Cm, 5H) 7!.36-7.45 (n 3H) 7. 63-7. 67 2H); MS [M-Br] 476; mp 11100.
Example 139 3 -(9-Hydroxy-9H-xanthene-9-carbonyloxy) -1-(3-phenyipropyl) -1-azo niabicyclo[2 .2 .2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 85 mg 41%. NM?. (DMSO-d6) :5 1.30 (in, 1K), 1.65 1K), 1.70-1.95 2K), 2.05 1K), 2.5-2.6 2K), 2.80 1K), 3.05-3.75 Cm,.7K), 5.05 1K), 7.1-7.45 (in, 12K), 7 .65-7. 70 (mn, 2K) MS [M-CF3C000P: 470.
Example 140 3 -(9-Hydroxy-9H-xanthene-9-carbonyloxy) -1-(4-phenylbutyl) -1-azoni abicyclo octane; trifJluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 84 mg NM?. (DMSO-d6) 5 1.30 1K), 1.4-1.85 Cm, 7H), 2.05 (mn, 1H), 2.5-2.6 2K), 2.80 '1K), 3.05-3.4 6K), 3.7 Cm, 1K), 5.05 Cm, 1K), 7.15-7.35 Cm, 10K), 7.4 1H), 7.65 Cm, 2H); MS [M-CF3COO]': 484.
Example 141 3(R) -(9-Hydroxy-9H-xanthene-9-carbonyloxy) -1-(2-thien-2-ylethyl) -1-a zoniabicyclo [2.2 octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 81 mng 39%. NM?. CDMSO-d6) :5 1. 30 1K), D 66 1.6 1H), 1.7-1.9(m, 2H), 2.05 1H), 2.75(m, 1H), 3.0(m, 1H), 3.1-3.2 2H), 3.3-3.6 5H), 3.8 1H), 5.05 1H), 6.95-7.0 00 2H), 7.15-7.3 5H), 7.45 3H), 7.65 2H); MS [M-CF3COO]*: 462.
Example 142 C-I 3(R) (9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(4-phenoxybutyl)-1-azo CI niabicyclo[2.2.2]octane; trifluoroacetate S The title compound was synthesised according to methods c and b. The C(1 yield of final step was 83 mg 37%. NMR (DMSO-d6): 6 1.3 1H), 1.5-1.9 7H), 2.05 1H), 2.6 1H), 2,8 1H), 3.1-3.45 (m, 7H), 3.75 1H), 4.0 2H), 5.05 1H) 6.95-7.0 3H) 7.15-7.45 9H), 7.65 2H); MS [M-CF3COO]*: 500.
Example 143 (9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azo niabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 102 mg 48%. NMR (DMSO-d6) 5 1.3 1H), 1.55-1.95 3H), 2.05 1H), 2,8 1H), 3.1 1H), 3.35-3.65 5H) 3.9 1H), 4.35 2H) 5.05 1H), 6.95 2H), 7.0-7.1 2H), 7.2 4H), 7.3-7.45 4H), 7.6 2H); MS [M- CF3COO]*: 472.
Exemple 144 1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-hydroxy-9H-xanthene-9-carbonyl oxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 99 mg 44%. NMR (DMSO-d6): 5 1.3 1H), 1.6 1H), 1.7-2.0 4H), 2.05 1H), 2.7 1H), 2.9 1H), 3.2-3.5 5H), 3.75-3.85 1H), 3.95 2H), 5.0 1H), 6.95 2H), 7.1-7.3 7H), 7.45 2H), 7.65 2H); MS [M-CF3COO] 504.
Exemple 145 67 3 (9-Hydroxy-9H-xanthene-9-carbonyloxy) (3-phenylallyl) -1-azoni S abicyclo octane; trifluoroacetate 00 The title compound was synthesised according to methods c and b. The yield of final step was 25 mg 12%. NMR (DMSO-d6) 1.25-1.30 (m, 1H), 1.55-1.95 (in, 3H), 2.10 Cm, 1K), 2.65-2.75 (in, 1H), 2.9 (mn, 1H), 3.25-3.50 2H), 3.75-3.8 (mn,1H), 3.95 (in, 2H), 4.2 1H), 5.0 (m, C1 1K), 6.35 Cm, 1H), 6.80 Cd, 1H), 7.05-7.50 8K), 7.60 4H); MS C1 M-CF3000J': 468.
ci Example 146 3(R) -(9-Methyl-9 -xanthene-9-carboiyloxy) -1-(3-phenoxypropyl) -1- -azoniabicyclo [2.2 octane; bromide The title compound was synthesised according to methods c and a. The yield of final step was 110 mg. NMR CIDMSO-d6) 6 1.4 Cm, 1K) 1.65 Cm, 1K) 1.75 1.95 Cm, 2H) 1.9 Cs, 3H), 2.05 2.15 Cm, 3H) 1.8 Cm, 1K), 3.15 Cm, 2K), 3.25.- 3.5 Cm, 5K), 3.85 Cm, 1K), 4.0 (t, 2H), 5.05 Cm, 1H), 6.95 7.0 Cm, 3K), 7.15 7.2 Cm, 4H), 7.3 7.4 Cm, 4K), 7.45 1H), 7.55 Cd, 1K) MS 484; mp 19500.
Example 147 3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-l-phenethyl-1azoniabicyclo [2 octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 19 mng, 20%. NMR CDMSQ.-d6) :6 1.4 Cm, 1K), 1.65 C(m, 1H), 1.8 1.95 C(m, 2K), 1.9 Cs, 3K), 2.15 Cm, 1K), 2.8 2.95 Cm, 3K), 3.15 Cd, 1K), 3.3 3.5 Cm, 5K), 4.9 Cm, 1K), 5.1 Cm, 1K), 7.15. Cm, 4H), 7.25S 7.4C m, 7K), 7.45 Cd, 1H), 7.55 (d, 1H); MS (M-CF 3 COOP*: 454.
Example 148 3(R) -(9-Methyl-9 -xanthene-9-carbonyloxy) -1-(2-phenoxyethyl)-2.azoniabicyclo octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 24 ing, 24%. NMR CDMSO-d6) 6 1.4 Cm, 1K), 1.65 Cm, 1K), 1.8 19 Cm2K, 1.9 Cs, 3K), 2.15 Cm,1), 29 1H) 3.25 1H), 3.4 3.65 5H), 3.85 1H), 4.35 (t, S 2H), 5.05 1H), 6.95 2H), 7.05 2H), 7.15 3H), 7.25 00 7.45 6H); MS [M-CF 3 COO]': 470.
Example 149 3(R) (9-Methyl-9 -xanthene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)- C 1-azoniabicyclo2 2 .2]octane; trifluoroacetate C The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 19%. 1 K- NMR (DMSO-d6): 5 1.4 1H), C- 1.65 1H), 1.75 1.95 7H), 2.15 1H), 2.8 1H), 3.05 3.25 4H), 3.3 3.5 4H), 3.85 1H), 5.05 1H), 7.15 4H), 7.35 2H), 7.45 7.6 4H), 7.7 1H), 8.0 (d, 2H); MS [M-CF3COO]*: 496.
Example 150 1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9carbonyloxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 25 mg, 24%. NMR (DMSO-d6): 6 1.4 1H), 1.65 1H), 1.75 1.95 2H), 1.9 3H), 1.95 2.1 2H), 2.15 1H), 2.8 1H), 3.1 1H), 3.25 3.5 5H), 3.8 (m, 1H), 4.0 2H), 5.05 1H), 6.95 2H), 7.15 6H), 7.35 2H), 7.5 (dd, 2H); MS [M-CF 3 COO]': 502.
Example 151 1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9carbonyloxy)-1-azoniabicyclof2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 16 mg, 15%. NMR (DMSO-d6): 6 1.4 1H), 1.65 1H), 1.75 1.95 2H), 1.9 3H), 2.0 2.15 3H), 2.8 1H), 3.1 1H), 7.05 1H), 7.1 7.4 8H), (dd, 2H); MS [M-CFCOO] 4 520.
Example 152 3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenylaminopropyl)- 69 1-azoniabicyclot2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The 00 yield of final step was 16 mg, 15%. 1 NMR (DMSO-d6): 6 1.35 1H), 1.6 1H), 1.7 1.9 4H), 1.9 3H), 2.1 1H), 2.7 (m, 1H), .2.95 3.05 3H), 3.1 3.4 6H), 3.75 1H), 5.0 (m, 1H), 5.6 1H), 6.55 3H), 7.05 7.15 6H), 7.3 2H), cr 7.45 2H); MS [M-CF 3 COO]': 483.
Example 153 C 1-3-(4-Hydroxyphenoxy)propyl)-3(R)-(9-methyl-9fH]-xanthene-9carbonyloxy)-1-azoniabicyclo2.2.2].2 octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 19 mg, 18%. NMR (DMSO-d6): 6 1.4 1H), 1.65 1H), 2.75 2.05 4H), 1.9 3H), 2.15 1H), 2.8 1H), 3.1 1H), 3.25 3.5 5H), 3.8 -3.95 3H), 5.05 1H), 6.65 6.8 4H), 7.2 4H), 7.35 2H), 7.5 (m, 2H), 9.0 OH); MS [M-CF 3 COO]': 500.
Example 154 1-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1azoniabicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesised according to methods c and b. The yield of final step was 14 mg, 14%. NMR (DMSO-d6): 6 1.4 1H), 1.65 1H), 1.75 1.95 2H), 1.9 3H), 2.1 1H), 2.9 (m, 1H), 3.2 3.5 6H), 3.75 3.95 3H), 4.5 2H), 5.05 (m, 1H), 7.15 4H), 7.3 7.5 9H); MS [M-CF3COO]': 484.
Example 155 1-(3-Phenoxypropyl)-3(R)-(9[H]-thioxanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; bromide The title compound was synthesised according to methods d and a. The yield of final step was 323 mg, 50%. NMR (DMSO-d6): 6 1.35 (m, 1H), 1. 65 1H), 1.70-1.95 2H), 2.0-2.2 3H), 2.75-2.90 (m, 1H), 3,12 1H), 3.25-3.50 5H), 3.80 1H), 4.0 2H), 5.0 1H), 5.6 1H), 6.94-7.0 3H), 7.22-7.41 6H), 7.45-7.64 4H); MS 486; mp 1570C.
00 Example 156 1-(3-phenylallyl)-3(R)-(10,11-Dihydro-5H-dibenzoIa,d)cycloheptene-5carbonyloxy)-1-azoniabicyclo[2.2.2]octane; bromide The title compound was synthesised according to methods d and a. The C yield of final step was 250 mg 94%. NMR (CDCl1,): 5 1.50-1.60 CK 1.60-1.80 1.90 2H), 2.30 1H), 2.65-2.80 (m, 2H), 2.90-3.20 3H), 3.50 1H), 3.60-3.90 3H), 4.20 1H), S 4.35-4.60 (doble dd, 2H), 5.10 1H), 5.15 1H), 6.05 (dd, 1H), 6.90-7.0 2H), 7.0-7.5 11H); MS 464; mp 1321C.
Example 157 1-(3-phenoxypropyl)-3(R) (10,11-Dihydro-5H-dibenzo[a,d]cycloheptene- 5-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; bromide The title compound was synthesised according to methods d and a. The yield of final step was 290 mg 94%. NMR (CDC13,): 5 1.45-1.60 (m, 1H), 1.65-1.80 1H), 1.80-2.0 2H), 2.0-2.20 3H), 2.80-3.0 3H), 3.15-3.30 2H), 3.30-3.45 1H), 3.45-3.80 3.85-4.0 2H), 4.20 1H), 5.10 1H), 5.20 1H), 6.80-6.90 2H), 6.90-7.0 1H), 7.10-7.30 8H), 7.40 2H); MS [M- 482; mp 1820C.
Example 158 3(R)-(5[H]-Dibenzo a,d]cycloheptene-5-carbonyloxy)-1-(3phenoxypropyl)-l-azoniabicyclo[2.2.2]octane; bromide The title compound was synthesised according to methods d and a. The yield of final step was 180 mg, 56%. NMR (DMSO-d6): 5 1.2 1H), 1.6 1H), 1.7 1.9 2H), 1.95 1H), 2.1 2H), 2.8 (m, 2.95 1H), 3.25 3.45 5H), 3.8 1H), 4.05 2H), 4.9 1H), 5.45 1H), 6.9 7.1 5H), 7.3 7.5 9H), 7.55 2H); MS [M-Brl*: 480; mp 1110C.
Example 159 3(R)-(5[H]-Dibenzoa,dlcycloheptene-5-carbonyloxy)-1-phenethyl-1- 0 71 azoniabicyclo[2.2.2]octane; bromide The title compound was synthesised according to methods d and a. The 00 yield of final step was 210 mg, 68%. NMR (DMSO-d6): 5 1.2 1H), 1.7 1.9 2H), 2.0 1H), 2.85 3.1 4H), 3.3 3.5 (m, 3.85 1H), 4.95 1H), 5.45 1H), 7.05 2H), 7.25 S 7.5 11H), 7.55 2H); MS [M-Br] 4 450; mp 248 0
C.
eC The Examples 160 to 164 illustrate pharmaceutical compositions S according to the present invention and procedure for their preparation.
Example 160 Preparation of a pharmaceutical composition: tablets Formulation: Compound of the present invention 5.0 mg Lactose 113.6 mg Microcrystalline cellulose 28.4 mg Light silicic 1.5 mg Magnesium stearate 1.5 mg Using a mixer machine, 15 g of the compound of the present invention was mixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose. The mixture was subjected to compression moulding using a roller compactor to give a flake-like compressed material. The flakelike compressed material was pulverized using a hammer mill, and the pulverized material was screened through a 20 mesh screen. A 4.5 g portion of light silicic anhydride and 4.5 g of magnesium stearate were added to the screened material and mixed. The mixer product was subjected to a tablets making machine equipped with a die/punch system of 7.5 mm in diameter, thereby obtaining 3,000 tablets each having 150 mg in weight.
Example 161 Preparation of a pharmaceutical composition: tablets coated Formulation: Compound of the present 5.0 mg Lactose 95.2 mg Corn 40.8 mg 00 Polyvinylpyrrolidone K2 7.5 mg Magnesium 1.5 mg 2.3 mg S Polyethylene glycol 0.4 mg C1 Titanium 1.1 mg CA Purified 0.7 mg In C- Using a fluidized bed granulating machine, 15 g of the compound of the present invention was mixed with 285.6 g of lactose and 122.4 g of corn starch. Separately, 22.5 g of polyvinylpyrrolidone was dissolved in 127.5 g of water to prepare a binding solution. Using a fluidized bed granulating machine, the binding solution was sprayed on the above mixture to give granulates. A 4.5 g portion of magnesium stearate was added to the obtained granulates and mixed. The obtained mixture was subjected to a tablet making machine equipped with a die/punch biconcave system of 6.5 mm in diameter, thereby obtaining 3,000 tablets, each having 150 mg in weight.
Separately, a coating solution was prepared by suspending 6.9 g of hydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol 6000, 3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water. Using a High Coated, the 3,000 tablets prepared above were coated with the coating solution to give film-coated tablets, each having 154.5 mg in weight.
Example 162 Preparation of a pharmaceutical composition: liquid inhalant Formulation: Compound of the present 400 ug Physiological 1 ml A 40 mg portion of the compound of the present invention was dissolved in 90 ml of physiological saline, and the solution was adjusted to a total volume of 100 ml with the same saline solution, dispensed in 1
I
ml portions into 1 ml capacity ampoule and then sterilized at 1150 for minutes to give liquid inhalant.
00 Example 163 Preparation of a pharmaceutical composition: powder inhalant Formulation: C1 Compound of the present 200 pg Cr 4,000 pg Cg A 20 g portion of the compound of the present invention was uniformly mixed with 400 g of lactose, and a 200 mg portion of the mixture was packed in a powder inhaler for exclusive use to produce a powder inhalant.
Example 164 Preparation of a pharmaceutical composition: inhalation aerosol.
Formulation: Compound of the present 200 pg Dehydrated (Absolute) ethyl alcohol 8,400 pg 1,1,1,2-Tetrafluoroethane (HFC-134A) 46,810 pg The active ingredient concentrate is prepared by dissolving 0.0480 g of the compound of the present invention in 2.0160 g of ethyl alcohol.
The concentrate is added to an appropriate filling apparatus. The active ingredient concentrate is dispensed into aerosol container, the headspace of the container is purged with Nitrogen or HFC-134A vapor (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valve. 11.2344 g of HFC-134A propellant is then pressure filled into the sealed container.
P:\Opc\MaI\2004\2493518 350 doc-20/12/04 Sn- 73A The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but O not the exclusion of any other integer or step or group of integers or V' steps.

Claims (19)

1. A compound which is (3R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3- phenoxypropyl)-l-azoniabicyclo[2.2.2]octane; X, S 5 wherein X- represents a pharmaceutically acceptable anion of a mono- or polyvalent acid. t
2. A compound which is (3R)-l-phenethyl-3-(9H-xanthene-9-carbonyloxy)-1- Sazoniabicyclo[2.2.2]octane; X' wherein X represents a pharmaceutically acceptable anion of a mono- or polyvalent acid.
3. A compound according to claim 1 or claim 2 wherein X' is an anion of a mineral acid or organic acid.
4. A compound according to claim 3 wherein the anion X' is selected from the group consisting of chloride, bromide, iodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate.
A compound according to claim 4 wherein the anion X" is selected from the group consisting of chloride, bromide, iodide, sulphate, nitrate, acetate, trifluoroacetate, maleate, oxalate, and succinate.
6. A compound according to claim 5 wherein the anion X' is selected from the group consisting of chloride, bromide, and trifluoroacetate.
7. A compound according to claim 1 or claim 2 wherein the anion X' represents bromide.
8. A compound according to claim 1 which is (3R)-(2-hydroxy-2,2-dithien-2- ylacetoxy)-l-(3-phenoxypropyl)-l-azoniabicyclo[2.2.2]octane bromide. P:\OPER\Mal\2005\ 2612130 313.doc-15/ z
9. A compound according to claim 2 which is (3R)-l-phenethyl-3-(9H-xanthene-9- tIt carbonyloxy)- 1-azoniabicyclo[2.2.2]octane bromide.
A pharmaceutical composition comprising a compound according to any one of S 5 claims 1 to 9. It
11. A pharmaceutical composition according to claim 10 further comprising a 32 0agonist.
12. A pharmaceutical composition according to claim 10, further comprising a steroid.
13. A pharmaceutical composition according to claim 10, further comprising an antiallergic drug.
14. A pharmaceutical composition according to claim 10, further comprising a phosphodiesterase IV inhibitor.
A pharmaceutical composition according to any one of claims 10 to 14 in the form of an inhalant.
16. A pharmaceutical composition according to claim 15 wherein the inhalant is selected from a liquid or powder inhalant or an inhalation aerosol.
17. A method for treating respiratory, urinary and/or gastrointestinal diseases comprises administering to a human or animal patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 9 or of a pharmaceutical composition according to claim
18. A method for treating COPD, chronic bronchitis, asthma or rhinits comprises administering to a human or animal patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 9 or of a pharmaceutical composition P:\OPER\Ma.20MS261262130 313.doc.15/1 S- 76- z according to any one of claims 10 to 16.
19. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for treating S 5 respiratory, urinary and/or gastrointestinal diseases. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical 0composition according to any one of claims 10 to 16, in the manufacture of a medicament for treating COPD, chronic bronchitis, asthma, or rhinits. DATED this 15 th day of November, 2005 Almirall Prodesfarma AG By DAVIES COLLISON CAVE Patent Attorneys for the Applicants
AU2005202144A 1999-07-14 2005-05-18 Quinuclidine derivatives and their use as muscarinic M3 receptor ligands Expired AU2005202144B2 (en)

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PCT/EP2000/006469 WO2001004118A2 (en) 1999-07-14 2000-07-07 Quinuclidine derivatives and their use as muscarinic m3 receptor ligands
AU64330/00A AU779881C (en) 1999-07-14 2000-07-07 Quinuclidine derivates and their use as muscarinic M3 receptor ligands
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US10034867B2 (en) 1999-07-14 2018-07-31 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
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